U.S. patent application number 12/080418 was filed with the patent office on 2008-10-30 for novel 2,3-benzodiazepine derivatives and their use as antipsychotic agents.
This patent application is currently assigned to Teva Pharmaceutical Industries Ltd.. Invention is credited to Ferenc Andrasi, Pal Berzsenyi, Emese Csuzdi, Katalin Horvath, Zoltan Nagy, Sandor Solyom, Istvan Sziraki.
Application Number | 20080269202 12/080418 |
Document ID | / |
Family ID | 39598447 |
Filed Date | 2008-10-30 |
United States Patent
Application |
20080269202 |
Kind Code |
A1 |
Csuzdi; Emese ; et
al. |
October 30, 2008 |
Novel 2,3-benzodiazepine derivatives and their use as antipsychotic
agents
Abstract
Disclosed are novel 2,3-benzodiazepine derivatives and methods
of making the same.
Inventors: |
Csuzdi; Emese; (Budapest,
HU) ; Solyom; Sandor; (Szigetmonostor, HU) ;
Berzsenyi; Pal; (Budapest, HU) ; Andrasi; Ferenc;
(Budapest, HU) ; Sziraki; Istvan; (Budapest,
HU) ; Horvath; Katalin; (Solymar, HU) ; Nagy;
Zoltan; (Isaszeg, HU) |
Correspondence
Address: |
LERNER, DAVID, LITTENBERG,;KRUMHOLZ & MENTLIK
600 SOUTH AVENUE WEST
WESTFIELD
NJ
07090
US
|
Assignee: |
Teva Pharmaceutical Industries
Ltd.
Petach Tikva
IL
|
Family ID: |
39598447 |
Appl. No.: |
12/080418 |
Filed: |
April 2, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60921532 |
Apr 2, 2007 |
|
|
|
60936631 |
Jun 20, 2007 |
|
|
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Current U.S.
Class: |
514/221 ;
540/567 |
Current CPC
Class: |
A61P 25/00 20180101;
C07D 413/04 20130101; C07D 401/06 20130101; C07D 419/04 20130101;
A61P 25/18 20180101; C07D 243/02 20130101; C07D 403/04 20130101;
C07D 413/06 20130101; C07D 417/04 20130101 |
Class at
Publication: |
514/221 ;
540/567 |
International
Class: |
A61K 31/551 20060101
A61K031/551; C07D 243/00 20060101 C07D243/00; A61P 25/00 20060101
A61P025/00 |
Claims
1. A compound of formula (I): ##STR00112## wherein R.sup.1 is
methyl and R.sup.2 is hydrogen; R.sup.3 is: a) a 5 or 6 membered
heterocyclic ring which is either aromatic, saturated or partially
saturated, said heterocyclic ring containing 1, 2, or 3 heteroatoms
selected from the group consisting of O, S, or N, said heterocyclic
ring optionally substituted by a C.sub.1-C.sub.3 alkyl group, a
C.sub.2-C.sub.3 alkenyl group or an oxo group, or ##STR00113##
wherein X is O or S; R.sup.11 is hydrogen, C.sub.1-C.sub.4 alkyl or
cycloalkyl or phenyl, and R.sup.12 is C.sub.1-C.sub.4 alkyl,
cycloalkyl, phenyl, or C.sub.1-C.sub.3 alkoxy, or R.sup.11 and
R.sup.12 together with the nitrogen atom to which they are attached
form an imidazolyl or a morpholinyl group, or ##STR00114## wherein
R.sup.13 is C.sub.1-C.sub.4 alkyl or phenyl; R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are each independently H, halogen,
C.sub.1-C.sub.3 alkyl, nitro, NR.sup.15R.sup.16 wherein R.sup.15
and R.sup.16 can each independently be H, C.sub.1-C.sub.3 alkyl,
C.sub.2-C.sub.5 acyl, C.sub.2-C.sub.5 alkoxycarbonyl,
aminocarbonyl, or C.sub.1-C.sub.5 alkylaminocarbonyl; and R.sup.9
and R.sup.10 are each independently C.sub.1-C.sub.3 alkoxy; or a
stereoisomer or pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R.sup.6 is nitro.
3. The compound of claim 1, wherein R.sup.6 is
NR.sup.15R.sup.16.
4. The compound of claim 3, wherein R.sup.15 and R.sup.16 are each
H.
5. The compound of claim 3, wherein R.sup.15 is H and R.sup.16 is
acetyl.
6. The compound of claim 1, wherein R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are each H.
7. The compound of claim 1, wherein R.sup.4, R.sup.7 and R.sup.8
are each H, and R.sup.5 is methyl.
8. The compound of claim 1, wherein the stereochemistry of the
carbon in the 4-position is in the R-conformation.
9. The compound of claim 1, wherein the stereochemistry of the
carbon in the 4-position is in the S-conformation.
10. The compound of claim 1, wherein R.sup.9 and R.sup.10 are each
methoxy.
11. The compound of claim 1, wherein R.sup.3 is a 5 or 6 membered
heterocyclic ring which is either aromatic, saturated or partially
saturated, said heterocyclic ring containing 1, 2, or 3 heteroatoms
selected from the group consisting of O, S, or N, said heterocyclic
ring optionally substituted by a C.sub.1-C.sub.3 alkyl group, a
C.sub.2-C.sub.3 alkenyl group or an oxo group.
12. The compound of claim 11, wherein R.sup.3 is a substituted or
unsubstituted thiazole, thiazoline, 4-thiazolinone, oxazole,
oxazoline, 1,3,4-thiadiazole, 1,3,4-oxadiazole,
1,2,4-thiadiazolin-3-one, 1,2,4-oxadiazole,
4H-1,2,4-oxadiazol-5-one, 1,4,2-oxathiazole, 1,3,4-triazole,
pyridine and 5,6-dihydro-4H-[1,3,4]thiadiazin-5-one.
13. The compound of claim 1, wherein R.sup.3 is: ##STR00115##
wherein X is O or S; R.sup.11 is hydrogen, C.sub.1-C.sub.4 alkyl or
cycloalkyl or phenyl, and R.sup.12 is C.sub.1-C.sub.4 alkyl,
cycloalkyl, phenyl, or C.sub.1-C.sub.3 alkoxy, or R.sup.11 and
R.sup.12 together with the nitrogen atom to which they are attached
form an imidazolyl or a morpholinyl group.
14. The compound of claim 13, wherein X is O.
15. The compound of claim 1, wherein R.sup.3 is: ##STR00116##
wherein R.sub.13 is C.sub.1-C.sub.4 alkyl or phenyl.
16. The compound of claim 11, wherein R.sup.3 is 1,3 thiazol-2-yl,
R.sup.9 and R.sup.10 are each methoxy, and the stereochemistry of
the carbon in the 4-position is in the R-conformation.
17. The compound of claim 16, wherein the compound is
[R]-1-(4-aminophenyl)-7,8-dimethoxy-4-methyl-3-(1,3-thiazol-2-yl)-4,5-dih-
ydro-3H-[2,3]benzodiazepine.
18. The compound of claim 16, wherein the compound is
[R]-1-(4-N-acetyl-aminophenyl)-7,8-dimethoxy-4-methyl-3-(1,3-thiazol-2-yl-
)-4,5-dihydro-3H-[2,3]benzodiazepine.
19. The compound of claim 11, wherein the compound is
[R]-1-(4-amino-3-methylphenyl)-7,8-dimethoxy-4-methyl-3-(1,2,4-oxadiazol--
3-yl)-4,5-dihydro-3H-[2,3]benzodiazepine.
20. The compound of claim 11, wherein the compound is
[R]-1-(4-amino-3-methylphenyl)-7,8-dimethoxy-4-methyl-3-(1,3,4-thiadiazol-
-2-yl)-4,5-dihydro-3H-[2,3]benzodiazepine.
21. The compound of claim 13, wherein the compound is
[R]-1-(4-aminophenyl)-7,8-dimethoxy-4-methyl-3-methylcarbamoyl-4,5-dihydr-
o-3H-[2,3]benzodiazepine.
22. The compound of claim 13, wherein the compound is
[R]-1-(4-amino-3-methylphenyl)-7,8-dimethoxy-4-methyl-3-methylcarbamoyl-4-
,5-dihydro-3H-[2,3]benzodiazepine.
23. A pharmaceutical composition comprising a compound of formula
(I) according to claim 1 or a stereoisomer or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
24. A method for treating psychotic disorders comprising
administering to a subject in need thereof a therapeutically
effective amount of a compound of claim 1 or a stereoisomer or a
pharmaceutically acceptable salt thereof.
25. The method of claim 24, wherein said psychotic disorders are
selected from the group consisting of schizophrenia,
schizophreniform disorder, schizoaffective disorder, delusional
disorder, brief psychotic disorder, shared psychotic disorder,
psychotic disorder due to a general medical condition,
substance-induced psychotic disorder, psychotic disorder not
otherwise specified, bipolar disorder and mood disorders with
psychotic symptoms.
26. The method of claim 25, wherein the compound administered is
[R]-1-(4-aminophenyl)-7,8-dimethoxy-4-methyl-3-(1,3-thiazol-2-yl)-4,5-dih-
ydro-3H-[2,3]benzodiazepine.
27. The method of claim 25, wherein the compound administered is
[R]-1-(4-N-acetyl-aminophenyl)-7,8-dimethoxy-4-methyl-3-(1,3-thiazol-2-yl-
)-4,5-dihydro-3H-[2,3]benzodiazepine.
28. The method of claim 25, wherein the compound administered is
[R]-1-(4-amino-3-methylphenyl)-7,8-dimethoxy-4-methyl-3-(1,2,4-oxadiazol--
3-yl)-4,5-dihydro-3H-[2,3]benzodiazepine.
29. The method of claim 25, wherein the compound administered is
[R]-1-(4-amino-3-methylphenyl)-7,8-dimethoxy-4-methyl-3-(1,3,4-thiadiazol-
-2-yl)-4,5-dihydro-3H-[2,3]benzodiazepine.
30. The method of claim 25, wherein the compound administered is
[R]-1-(4-aminophenyl)-7,8-dimethoxy-4-methyl-3-methylcarbamoyl-4,5-dihydr-
o-3H-[2,3]benzodiazepine.
31. The method of claim 25, wherein the compound administered is
[R]-1-(4-amino-3-methylphenyl)-7,8-dimethoxy-4-methyl-3-methylcarbamoyl-4-
,5-dihydro-3H-[2,3]benzodiazepine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the filing date of
U.S. Provisional Patent Application No. 60/921,532 filed Apr. 2,
2007; and U.S. Provisional Patent Application No. 60/936,631 filed
Jun. 20, 2007, the disclosures of which are hereby incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0002] Conventional antipsychotics (for example, chlorpromazine or
haloperidol) exert their effect by the antagonism of the
dopamine-D.sub.2 receptor. However, about 30% of psychotic patients
are refractory to the current antidopamine therapy. Thus, atypical
antipsychotics having better side-effect profiles, which differ in
mechanism from the classical ones, have gained special
importance.
[0003] Within the family of 2,3-benzodiazepines, several groups of
compounds have been reported to have high therapeutic value in
different therapeutic areas related to the central nervous system
(CNS) (for reviews see, for example, Horvath, E. J., Horvath, K. et
al, Progress in Neurobiology 2000, 60, 309 and Solyom, S., Tarnawa,
I. Curr. Pharm. Des. 2002, 8, 9-13).
[0004] Among the 5H-[2,3]benzodiazepines, the compound
7,8-dimethoxy-1-(3,4-dimethoxyphenyl)-5-ethyl-4-methyl-5H-[2,3]benzodiaze-
pine (Grandaxin) is a non-sedative anxiolytic. Hungarian Patent No.
179 018 describes the anxiolytic compound
7,8-dimethoxy-1-(3-chlorophenyl)-5H-[2,3]benzodiazepine (Girisopam)
as a follow-up compound. Another related compound,
1-(4-aminophenyl)-7,8-dimethoxy-5H-[2,3]benzodiazepine (Nerisopam),
is disclosed in Hungarian Patent No. 191 698 as having some
definite antipsychotic character in addition to having an
anxiolytic effect.
[0005] Hungarian Patent Nos. 221 508, 224 435, and 224 438 disclose
5H-[2,3]benzodiazepine derivatives bearing substituted styryl
groups in position 1 and alkoxy or methylenedioxy substituents in
positions 7,8. These compounds are disclosed to have different CNS
activities, for example, anxiolytic, antiaggresive and
antipsychotic effects.
[0006] A quite different biological activity profile was shown when
the 7,8-dimethoxy substituents of Nerisopam, were replaced with a
methylenedioxy group. The compound
5-(4-aminophenyl)-8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine
had an anticonvulsive effect and was found to be a non-competitive
AMPA antagonist belonging to the family of glutamate antagonists
(Tarnawa et al. Eur. J. Pharmacol, 1989, 167, 193; Smith, S. E.,
Meldrum, B. S. Eur. J. Pharmacol 1990, 187, 131; U.S. Pat. No.
4,614,740).
[0007] Compounds with similar AMPA antagonist activity were found
in 2,3-benzodiazepine systems containing a dioxolane ring at the
7,8 position or in systems containing halogen atoms at positions 7
and/or 8. Moreover, substitution of a methoxy group at either
position 7 or 8 of the 4,5-dihydro-3H-[2,3]benzodiazepine or
3H-[2,3]benzodiazepine systems and further bearing an acyl
substituent in position 3, also showed similar AMPA antagonist
activity. Such compounds are described, for example, in Hungarian
Patent Nos. 191 698; 191 702; 206 719; 219 777; in the U.S. Pat.
Nos. 5,459,137; 5,536,832; in British Patent No. 2 311 779, as well
as WO 96/04 283, WO 97/28 135 (U.S. Pat. No. 6,200,970), WO 99/07
707, WO 99/07 708, WO 01/04 122 and WO 05/01 2265.
[0008] Other 2,3-benzodiazepine derivatives with AMPA antagonist
activities, which bear a 5- or 6-membered heterocyclic substituent
at N-3 and having a methylenedioxy, halogen, or methoxy substituent
at positions 7 or 8 have been disclosed. See, for example, U.S.
Pat. Nos. 5,795,886 and 6,858,605.
[0009] U.S. Pat. No. 6,887,867 (hereinafter the "'867 Patent") (PCT
Application No. WO-01/98280) discloses, 2,3-benzodiazepine
derivatives as exerting non-NMDA excitatory aminoacid (AMPA)
antagonist activity. However, neither the identification data, the
physical characteristics, or the process of preparation of the
claimed 2,3-benzodiazepines bearing two C.sub.1-C.sub.3 alkoxy
substituents in positions 7,8 is disclosed in the '867 patent.
SUMMARY OF THE INVENTION
[0010] The invention relates to new 2,3-benzodiazepine derivatives
of formula (I), isomers and acid addition salts thereof,
##STR00001##
wherein R.sup.1 is methyl and R.sup.2 is hydrogen; R.sup.3
represents one of the following: (a) a 5 or 6 membered heterocyclic
ring which is either aromatic, saturated or partially saturated,
said heterocyclic ring containing 1, 2, or 3 heteroatoms selected
from the group consisting of O, S, or N, said heterocyclic ring
optionally substituted by a C.sub.1-C.sub.3 alkyl group, a
C.sub.2-C.sub.3 alkenyl group or an oxo group,
##STR00002##
wherein X is O or S; R.sup.11 is hydrogen, C.sub.1-C.sub.4 alkyl or
cycloalkyl or phenyl, and R.sup.12 is C.sub.1-C.sub.4 alkyl,
cycloalkyl, phenyl, or C.sub.1-C.sub.3 alkoxy, or R.sup.11 and
R.sub.12 together with the nitrogen atom to which they are attached
form an imidazolyl or a morpholinyl group, or
##STR00003##
wherein R.sup.13 is C.sub.1-C.sub.4 alkyl or phenyl; R.sup.4,
R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently H,
halogen, C.sub.1-C.sub.3 alkyl, nitro, NR.sup.15R.sup.16 wherein
R.sup.15 and R.sup.16 can each independently be H, C.sub.1-C.sub.3
alkyl, C.sub.2-C.sub.5 acyl, C.sub.2-C.sub.5 alkoxycarbonyl,
aminocarbonyl, or C.sub.1-C.sub.5 alkylaminocarbonyl; and R.sup.9
and R.sup.10 are each independently C.sub.1-C.sub.3 alkoxy.
[0011] The invention also discloses pharmaceutical compositions
comprising a compound of formula (I) as the active ingredient, or a
stereoisomer or a pharmaceutically acceptable salt thereof. The
composition may further comprise a pharmaceutically acceptable
carrier, e.g., solvents, diluents, and fillers.
[0012] The compounds of formula (I) are suitable for treating
psychotic disorders, including schizophrenia, schizophreniform
disorder, schizoaffective disorder, delusional disorder, brief
psychotic disorder, shared psychotic disorder, psychotic disorder
due to a general medical condition, substance-induced psychotic
disorder, psychotic disorder not otherwise specified, bipolar
disorder and mood disorders with psychotic symptoms.
[0013] Accordingly, a further aspect of the present invention is
directed to methods of treating psychotic disorders comprising
administering to a subject in need thereof a therapeutically
effective amount of a compound of formula (I) or a stereoisomer or
a pharmaceutically acceptable salt thereof.
[0014] Applicants have surprisingly found that 2,3-benzodiazepine
derivatives bearing a methoxy substituent at each of positions 7
and 8, in addition to having a carbamoyl group at N-3
(2,3-benzodiazepine numbering), do not exhibit AMPA antagonism. On
the other hand, applicants have also discovered that these
compounds show antipsychotic activity.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 shows, comparatively, the effect of clozapine,
compound 121 and compound 183 on PCP-induced disruption of
pre-pulse intensity. Data represent mean .+-.SEM.
[0016] FIG. 2 shows, comparatively, the effect of compounds 121
("CMP A") and 183 ("CMP B") on locomotor behavior in mice. Data
represent mean .+-.SEM.
DETAILED DESCRIPTION
[0017] The invention provides new 2,3-benzodiazepine derivatives of
formula (I), the isomers as well as the acid addition salts
thereof,
##STR00004##
wherein R.sup.1 is methyl and R.sup.2 is hydrogen, R.sup.3
represents one of the following: (a) a 5 or 6 membered heterocyclic
ring which is either aromatic, saturated or partially saturated,
said heterocyclic ring containing 1, 2, or 3 heteroatoms selected
from the group consisting of O, S, or N, said heterocyclic ring
optionally substituted by a C.sub.1-C.sub.3 alkyl group, a
C.sub.2-C.sub.3 alkenyl group or an oxo group;
##STR00005##
wherein X represents O or S; R.sup.11 is hydrogen, C.sub.1-C.sub.4
alkyl, cycloalkyl or phenyl, and R.sup.12 is C.sub.1-C.sub.4 alkyl,
cycloalkyl, phenyl, or C.sub.1-C.sub.3 alkoxy, or R.sup.11 and
R.sub.12 together with the nitrogen atom to which they are attached
form an imidazolyl or a morpholinyl group; or
##STR00006##
wherein R.sup.13 represents C.sub.1-C.sub.4 alkyl or phenyl;
R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each
independently H, halogen, C.sub.1-C.sub.3 alkyl, nitro,
NR.sup.15R.sup.16 wherein R.sup.15 and R.sup.16 can each
independently be H, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.5 acyl,
C.sub.2-C.sub.5 alkoxycarbonyl, aminocarbonyl, or C.sub.1-C.sub.5
alkylaminocarbonyl; and R.sup.9 and R.sup.10 are each independently
C.sub.1-C.sub.3 alkoxy.
[0018] The term alkyl group encompasses both straight and branched
chain alkyl groups. The meaning of alkenyl group can be vinyl,
1-propenyl or 2-propenyl group. Halogen atoms can be fluorine,
chlorine, bromine or iodine atom. The amino group can be
unsubstituted or substituted with one or two alkyl groups as well
as acylated with aliphatic or aromatic carboxylic acids or any kind
of carbonic acid esters.
[0019] The heterocyclic substituent of the 2,3-benzodiazepine ring
as R.sub.3 can be, among others, thiazole, thiazoline,
4-thiazolinone, oxazole, oxazoline, 1,3,4-thiadiazole,
1,3,4-oxadiazole, 1,2,4-thiadiazolin-3-one, 1,2,4-oxadiazole,
4H-1,2,4-oxadiazol-5-one, 1,4,2-oxathiazole, 1,3,4-triazole,
pyridine and 5,6-dihydro-4H-[1,3,4]thiadiazin-5-one.
[0020] In case of compounds of formula (I), the term "isomers" or
"stereoisomers" includes both R and S enantiomers, as well as E and
Z isomers, if applicable. Furthermore, "isomers" shall include
diasteromers, tautomers and mixtures thereof, for example
racemates.
[0021] Salts of the compounds of formula (I) relate to
physiologically and/or pharmaceutically acceptable salts formed
with inorganic or organic acids. Suitable inorganic acids can be,
for example, hydrochloric acid, hydrobromic acid, phosphoric acid
or sulfuric acid. Suitable organic acids can be, for example,
formic acid, acetic acid, maleic acid, fumaric acid, succinic acid,
lactic acid, tartaric acid, citric acid or methanesulfonic
acid.
[0022] In some embodiments, R.sup.9 and R.sup.10 are both methoxy
and R.sup.3 is a 5- or 6-membered heterocyclic ring which is either
aromatic, saturated or partially saturated, wherein the
heterocyclic ring contains 1, 2, or 3 heteroatoms selected from the
group consisting of O, S, or N, and wherein said heterocyclic ring
is optionally substituted by a C.sub.1-C.sub.3 alkyl group, a
C.sub.2-C.sub.3 alkenyl group or an oxo group.
[0023] In other embodiments, R.sup.9 and R.sup.10 are both methoxy
and R.sup.3 a substituted or unsubstituted thiazole, thiazoline,
4-thiazolinone, oxazole, oxazoline, 1,3,4-thiadiazole,
1,3,4-oxadiazole, 1,2,4-thiadiazolin-3-one, 1,2,4-oxadiazole,
4H-1,2,4-oxadiazol-5-one, 1,4,2-oxathiazole, 1,3,4-triazole,
pyridine or 5,6-dihydro-4H-[1,3,4]thiadiazin-5-one.
[0024] In yet other embodiments, R.sup.9 and R.sup.10 are both
methoxy and R.sup.3 is
##STR00007##
wherein X is O or S; R.sup.11 is hydrogen, C.sub.1-C.sub.4 alkyl or
cycloalkyl or phenyl, and R.sup.12 is C.sub.1-C.sub.4 alkyl,
cycloalkyl, phenyl, or C.sub.1-C.sub.3 alkoxy, or R.sup.11 and
R.sup.12 together with the nitrogen atom to which they are attached
form an imidazolyl or a morpholinyl group.
[0025] In yet other embodiments, R.sup.9 and R.sup.10 are both
methoxy and R.sup.3 is
##STR00008##
wherein R.sup.13 is C.sub.1-C.sub.4 alkyl or phenyl.
[0026] In yet further embodiments, R.sup.3 is 1,3-thiazol-2-yl,
R.sup.9 and R.sup.10 are each methoxy, and the stereochemistry of
the carbon in the 4-position is in the R-conformation.
[0027] One or more representative compounds of formula (I) of the
invention include the following:
[R]-1-(4-aminophenyl)-7,8-dimethoxy-4-methyl-3-(1,3-thiazol-2-yl)-4,5-dih-
ydro-3H-[2,3]benzodiazepine;
[R]-1-(4-N-acetylaminophenyl)-7,8-dimethoxy-4-methyl-3-(1,3-thiazol-2-yl)-
-4,5-dihydro-3H-[2,3]benzodiazepine;
[R]-1-(4-amino-3-methylphenyl)-7,8-dimethoxy-4-methyl-3-(1,2,4-oxadiazol--
3-yl)-4,5-dihydro-3H-[2,3]benzodiazepine;
[R]-1-(4-amino-3-methylphenyl)-7,8-dimethoxy-4-methyl-3-(1,3,4-thiadiazol-
-2-yl)-4,5-dihydro-3H-[2,3]benzodiazepine;
[R]-1-(4-aminophenyl)-7,8-dimethoxy-4-methyl-3-methylcarbamoyl-4,5-dihydr-
o-3H-[2,3]benzodiazepine;
[R]-1-(4-aminophenyl)-7,8-dimethoxy-4-methyl-3-methylcarbamoyl-4,5-dihydr-
o-3H-[2,3]benzodiazepine;
[R]-1-(4-amino-3-methylphenyl)-7,8-dimethoxy-4-methyl-3-methylcarbamoyl-4-
,5-dihydro-3H-[2,3]benzodiazepine; and the acid addition salts
thereof.
[0028] The compounds of formula (I) can be prepared in the
following manner from a compound of formula (II)
##STR00009##
wherein the meaning of R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9 and R.sup.10 is as defined above and the
heterocycle, corresponding to R.sup.3 of formula (I), is linked by
known methods.
[0029] Alternatively, a compound of general formula (II) can be
reacted with an active derivative of a carbamoic acid of formula
(III)
R.sup.11R.sup.12N--CX-Z (III)
wherein the meanings of R.sup.11 and R.sup.12 are as defined above
and Z is halogen atom or a leaving group. Alternatively, a compound
of general formula (II) is reacted with an isocyanate or an
isothiocyanate of formula (IV)
R.sup.11--N.dbd.C.dbd.X (IV)
wherein the meanings of R.sup.11 and X are as defined above.
[0030] Alternatively, a compound of formula (II) is reacted with an
activated carbonic acid derivative of formula (V)
R.sup.13--O--CO-Z (V)
wherein the meaning of R.sup.13 is as defined above and Z is
halogen atom or a leaving group.
[0031] Alternatively, a compound of formula (I) wherein the
meanings of R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9 and R.sup.10 is as defined above and R.sup.3 is
such a group R.sup.13O--CO-- wherein R.sup.13 is a phenyl group, or
the meaning of R.sup.3 is such a group R.sup.11R.sup.12N--CO--
wherein R.sup.11 and R.sup.12 together mean an imidazolyl group,
can be formed by reacting a compound of formula (II) with an amine
of general formula (VI)
R.sup.11R.sup.12NH (VI)
wherein the meanings of R.sup.11 and R.sup.12 are as defined above,
other than an imidazolyl group.
[0032] To synthesize the compounds of the invention, a compound of
formula (VII) or an isochromenilium salt of formula (VIIa) which is
formed from a compound of formula (VII)
##STR00010##
wherein the meaning of R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9 and R.sup.10 is as defined above, is
reacted with a compound of formula (VIII) or (IX)
R.sup.3--NH--NH.sub.2 (VIII)
R.sup.14--NH--NH.sub.2 (IX)
wherein the meaning of R.sup.3 is as defined above and the meaning
of R.sup.14 is C.sub.2-C.sub.8 alkoxycarbonyl or aryl
alkoxycarbonyl group, to obtain the compounds of formulas (X) or
(XI).
##STR00011##
[0033] The hydroxyl group of the compounds of formulas (X) or (XI)
is transformed into a sulfonate ester, and the latter intermediate
is subjected to ring-closure resulting in compounds of formulas (I)
or (XII)
##STR00012##
by reaction with a strong base.
[0034] In the compounds of formula (XII), the R.sup.14 group can
then cleaved to produce a compound of formula (II), which is
converted into compounds of formula (I) according to methods
described above. Then, if desired, the nitro group of a compound of
formula (I) is reduced. Alternatively, the amino group is acylated,
alkylated or, after diazotation, is exchanged with a halogen or
hydrogen atom. The halogen atom of the resulting acyl group is
exchanged with an amino group or the resulting a carbonyl group is
thionated to give a thiocarbonyl derivative.
[0035] The compounds of formula (II) and (XII) are chiral compounds
and therefore formulas (II) and (XII) refer to either of the
individual enantiomers or mixtures thereof.
[0036] The hemiketal type compounds of formula (VII) as well as the
hydrazone derivatives of formula (X) and (XI) represent different
stereoisomers and they refer to all possible individual
stereoisomers and mixtures thereof.
[0037] The R.sup.14 group can be a C.sub.2-C.sub.8 alkoxycarbonyl
or a benzyloxycarbonyl group. The cleavage of the R.sup.14 group
can be achieved either by acidic or hydrogenolytic methods.
A leaving group, during the above transformations, can be without
limitation a substituted or unsubstituted benzenesulfonate group,
phenoxy group or an alkanesulfonate group, especially
methanesulfonate group or an imidazolyl group.
[0038] A racemic starting material of formula (II) and related
racemic derivatives of 7,8-dimethoxy (or
dialkoxy)-4-methyl-1-(substituted)
phenyl-4,5-dihydro-3H-[2,3]benzodiazepines are known in the
scientific literature and are described in Belgian Patent No.
892395 (U.S. Pat. No. 4,423,044). See also HU 186 760.
[0039] Optically active compounds of formula (II) can be
synthesized from an optically active, substituted
phenyl-isopropanol according to Anderson et al. (J. Am. Chem. Soc.
1995, 117, 12358). Thus, e.g. starting from
(S)-3,4-dimethoxyphenyl-isopropanol (Erdelyi, B. et al.
Tetrahedron: Asymmetry 2006, 17, 268), a hemiketal of formula (VII)
can be synthesized according to methods described by Anderson et
al., supra., and reacting this compound instead of acethydrazid
with an alkoxycarbonyl-hydrazid, such as tert-butyl carbazate,
containing an easily removable tert-butoxycarbonyl group, the
hydrazon of formula (XI) can be obtained. The hydrazon can be
transformed, e.g. with methanesulfonyl chloride in the presence of
triethylamine, into a mesyloxy derivative. This compound is then
treated with base, for example sodium hydroxide in alcoholic
solution, to yield the benzodiazepine derivative of formula (XII)
in a ring closure reaction. The R.sup.14 substituent of the N-3
atom (2,3-benzodiazepine numbering) is then cleaved, e.g. by
hydrolysis or another suitable method, to yield the desired
compound of formula (II). The cleavage of the tert-butoxycarbonyl
group may be carried out with trifluoroacetic acid, hydrochloric
acid, or zinc bromide in dichloromethane. Thus, regarding the
inversion of configuration during the synthetic sequence, e.g. from
a substituted (S)-phenyl-isopropanol, a compound of formula (II)
with (R) configuration can be formed. Whereas, if e.g.
3,4-dimethoxyphenyl-acetone is reduced microbiologically with the
strain Debaryomyces carsonii IDR 513, similarly to the method
described by Anderson et al., supra.,
(R)-3,4-dimethoxyphenyl-isopropanol is formed, which after similar
transformations as described before, gives rise to the formation of
benzodiazepines of formula (II) with (S) configuration.
[0040] In those molecules of formula (I), wherein the R.sup.3
substituent is a heterocycle, the heterocyclic moiety can be built
up starting from compounds of formula (II) according to methods
known in the art relating to heterocyclic chemistry.
[0041] Some of the compounds of formula (I), wherein R.sup.3 is a
sulfur containing heterocycle, can be synthesized e.g. from
4,5-dihydro-3H-[2,3]benzodiazepine derivatives substituted with a
thiocarbamoyl group at position 3 of the benzodiazepine ring. These
thiocarbamoyl compounds can be obtained from
4,5-dihydro-3H-[2,3]benzodiazepine derivatives of formula (II), for
example with potassium thiocyanate in acetic acid medium. The thus
obtained 4,5-dihydro-3-thiocarbamoyl-3H-[2,3]benzodiazepines, when
reacted with .alpha.-halo-ketones or .alpha.-halo-aldehyde acetals
give 2-thiazolyl substituted 2,3-benzodiazepine derivatives. In an
analogous reaction, if 2-halo-carboxylic acid esters are used
instead of the .alpha.-halo oxo-compound, the appropriate
compounds, containing a 3-thiazolinone ring, are formed. Similarly,
if the 3-thiocarbamoyl-2,3-benzodiazepine intermediate is reacted
with 1,2-dibromoethane or .beta.-bromoethylamine, benzodiazepines
substituted with a 2-thiazoline ring are formed.
[0042] The compounds of formula (I) containing a 1,3,4-thiadiazole
group as the R.sup.3 substituent can be synthesized for example as
follows: First the 3,5-dihydro-3H-[2,3]benzodiazepine of formula
(II) is reacted with thiophosgene in the presence of triethylamine
to give the corresponding thiocarboxylic acid chloride and the
latter is then reacted with hydrazine to yield the thiocarboxylic
acid hydrazide derivatives. Latter
2,3-benzodiazepine-3-carbothiohydrazide derivatives are reacted
with an acid anhydride or chloride to attain
carbothio-N-acylhydrazides. The ring closure of the
carbothio-N-acylhydrazides is promoted by further acid treatment to
yield the [1,3,4]thiadiazol-2-yl-2,3-benzodiazepines. In another
synthetic procedure of the latter compounds the above mentioned
intermediate thiocarboxylic acid chloride is first reacted with an
acid hydrazide and the resulting carbothiohydrazide derivative
containing an acyl group on the terminal N-atom is treated with
acid to result in the cyclic product.
[0043] If the above described intermediate N-acyl-thiocarboxylic
acid hydrazide derivatives are treated with a sulfur binding agent,
for example mercury (II) acetate, then benzodiazepines of formula
(I) can be obtained, wherein the R.sup.3 substituent is an
[1,3,4]oxadiazole ring.
[0044] Compounds of formula (I), wherein R.sup.3 is a six membered
2-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl) group, can be
prepared by reacting the aforementioned
4,5-dihydro-[2,3]benzodiazepine-3-carbothiohydrazide intermediate
with bromoacetic acid ester.
[0045] Reacting a 4,5-dihydro-[2,3]benzodiazepine-3-thiocarboxylic
acid chloride with hydroxylamine the corresponding thiohydroxamic
acid can be obtained and the latter can be transformed into a
heterocyclic compound by reacting with a bifunctional alkylating
reagent. For example compounds of formula (I), wherein R.sup.3 is a
[1,4,2]oxathiazol-3-yl group can be obtained when an above
mentioned 4,5-dihydro-3H-2,3-benzodiazepine-3-thiohydroxamic acid
is reacted with methylene iodide.
[0046] The compounds of formula (I) with
(3-oxo-2,3-dihydro-[1,2,4]thiadiazol-5-yl) group as the R.sup.3
substituent can be prepared, for example, by reacting the
unsubstituted compounds of formula (II) with phenoxycarbonyl
isothiocyanate, then the resulting
3-(phenoxycarbonyl-thiocarbamoyl)-benzodiazepine is transformed
into 3-(N'-alkyl-carbamoyl)-thiocarbamoyl-benzodiazepine with
primary amines and the latter is reacted with bromine to accomplish
the ring closure between the sulfur and the nitrogen atoms.
[0047] The compounds of formula (I) with a
(4,5-dihydro-oxazol-2-yl) group as an R.sup.3 substituent can be
synthesized by reacting the compound of formula (II) with
chloroethyl isocyanate to give the urea intermediate, which is then
heated in the presence of sodium iodide and potassium carbonate in
dimethylformamide to accomplish ring closure.
[0048] Compounds of formula (I) containing an unsubstituted or
5-alkyl substituted ([1,2,4]oxadiazole-3-yl) group as R.sup.3
substituent can be synthesized for example from
3-cyano-4,5-dihydro-3H-[2,3]benzodiazepines. The latter compounds
are obtained from compounds of formula (II) with cyanogen bromide.
This nitrile compound is first treated with hydroxylamine and the
amidoxime which is obtained is reacted either with a trialkyl
orthoformate in the presence of a catalytic amount of hydrochloric
acid to give the unsubstituted [1,2,4]oxadiazole derivative or when
instead of the orthoformate a carboxylic acid anhydride or chloride
is applied then the corresponding
(5-alkyl-[1,2,4]oxadiazol-2-yl)-benzodiazepine is formed.
[0049] Alternatively, if an above-described intermediate amidoxime
type compound is reacted with, for example,
1,1'-carbonyldiimidazole then compounds of formula (I) can be
prepared wherein R.sup.3 is a (5-oxo-4H-1,2,4-oxadiazol-2-yl)
group.
[0050] The compounds of formula (I) wherein a 1,2,4-triazolyl group
is R.sup.3 substituent can be synthesized from a
3-thiocarbamoyl-[2,3]benzodiazepine derivative by reacting with
methyl iodide then the obtained S-methyl compound is condensed with
hydrazine and the intermediate formed is then treated with a
carboxylic acid anhydride or chloride.
[0051] Compounds of formula (I), wherein R.sup.3 is a (2-oxazolyl)
group, can be synthesized by reacting a
3-phenoxycarbonyl-4,5-dihydro-3H-[2,3]benzodiazepine with an
amino-ketone-acetal derivative, then the obtained urea derivative,
possessing a ketone-acetal side chain on the terminal N-atom, can
be brought to ring closure by treatment with a mixture of
methanesulfonic acid and phosphorous pentoxide to yield the
corresponding
3-(oxazol-2-yl)-4,5-dihydro-3H-[2,3]benzodiazepine.
[0052] Other illustrative processes for the synthesis of compounds
of formula (I) are those where a hemiketal of formula (VII) is
reacted with a heterocyclic reagent substituted with a hydrazine
group in the presence of an acid as a catalyst. The condensation
reaction can be carried out in the presence of hydrochloric acid as
a catalyst by heating with a Dean-Stark apparatus. It can be
advantageous in some instances to first transform the hemiketal
into an isochromenilium salt of formula (VIIa) with a mineral acid
such as perchloric acid and reacting the latter with a hydrazine
reagent in isopropanol. The obtained hydrazones of formula (X) are
generally formed as a mixture of stereoisomers. They can be further
reacted with methanesulfonyl chloride, for example, in
dichloromethane in the presence of triethylamine, and the mesylate
obtained after isolation can be treated with a concentrated
solution of a base in an alcohol or a mixture of
alcohol-dichloromethane. The ring closure reaction can be achieved
for example, by the Mitsunobu reaction (Mitsunobu, O. Synthesis
1981, 1) as well.
[0053] Compounds of formula (I) with a carbamoyl group as the
R.sup.3 substituent can be synthesized by acylating a compound of
formula (II) with an active derivative of a carbamic acid, such as
a chloride. Those compounds of formula (I), in which R.sup.3 group
is R.sup.11R.sup.12NCX, where X stands for an oxygen or sulfur
atom, and R.sup.11 is hydrogen, can be synthesized conveniently by
acylation with an isocyanate or isothiocyanate.
[0054] Another synthetic procedure for the preparation of compounds
of formula (I) wherein R.sup.3 is a carbamoyl group of formula
R.sup.11R.sup.12NCO is the following: a compound of formula (II) is
reacted first with a phenoxycarbonyl chloride in the presence of an
acid binding agent, such as triethylamine, to give a
4,5-dihydro-3-phenoxycarbonyl-3H-[2,3]benzodiazepine derivative.
The latter compound is then reacted with a primary or secondary
amine to substitute the phenoxy group.
[0055] If a compound of formula (I) containing as R.sup.3 a group
of formula R.sup.11R.sup.12NCS is desired then it can be
synthesized from another compound of formula (I), wherein R.sup.3
stands for R.sup.11R.sup.12NCO. A thionation reaction can be
performed with a Lawesson reagent or phosphorous pentasulfide in an
organic solvent.
[0056] Compounds of formula (I) wherein R.sup.3 is a group of
formula R.sup.13o--CO, wherein R.sup.13 is an alkyl or phenyl
group, can be synthesized from compounds of formula (II) by
acylation with the corresponding chlorocarbonic acid ester in the
presence of an acid binding agent such as triethylamine.
[0057] If desired, the compound of formula (I) obtained by
different methods can be transformed into other compounds of
formula (I) with further reactions. For example the NH group of an
N-containing heterocyclic compound can be alkylated by known
methods. The latter transformation for example in the case of a
triazolyl compound, can be carried out with methyl iodide in the
presence of potassium tert-butoxide.
[0058] The reduction of the nitro group in the compounds of formula
(I) is generally carried out in polar solvents at room temperature
or at elevated temperature in the presence of catalysts such as
Raney-nickel, platinum or palladium. Besides gaseous hydrogen,
other hydrogen sources e.g., hydrazine hydrate, ammonium formate,
potassium formate or cyclohexene can also be applied. The nitro
group can be reduced, for example, with tin in the presence of an
acid or with tin (II) chloride by heating in an alcohol as well.
The amino group can be further derivatized by known methods, for
example alkylation, acylation or Sandmeyer reaction.
[0059] The new 2,3-benzodiazepine atypical antipsychotic agents of
formula (I) of the present invention are useful for the treatment
of psychotic disorders, including the treatment of schizophrenia
and bipolar disorder. The compounds can also be used for treating
schizoaffective disorder, schizophreniform disorder, mood disorders
with psychotic symptoms, shared psychotic disorders, and brief
psychotic disorder. They may improve functioning in patients with
dementia or delirium when psychotic symptoms are present.
Additional diseases in which these compounds can be used are
aggression, substance-induced psychotic disorders, psychotic
disorders due to a general medical condition, and personality
disorders (borderline).
[0060] Hence, the invention provides a method of treating psychotic
disorders comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of formula (I) or a
stereoisomer or a pharmaceutically acceptable salt thereof. A
therapeutically effective amount is a dosage of the compound of
formula (I) sufficient to provide a medically desirable result. The
therapeutically effective amount of a compound of formula (I) is
that amount effective to treat the psychotic disorder or to prevent
the onset of diseases, such as aggression or mood disorders.
[0061] The factors involved in determining an effective amount are
well known to those of ordinary skill in the art and can be
addressed with no more than routine experimentation. It is
generally preferred that a maximum dose of the compounds of the
invention (alone or in combination with other therapeutic agents)
be used, that is, the highest safe dose according to sound medical
judgment. It will be understood by those of ordinary skill in the
art however, that a patient may insist upon a lower dose or
tolerable dose for medical reasons, psychological reasons or for
virtually any other reasons.
[0062] The dosage of the active ingredient depends on the route of
administration, the type and severity of the disease as well as the
weight and age of the patient. The daily dose for adult patients
generally ranges from about 0.1 mg to about 500 mg, preferably from
about 1 mg to about 100 mg, in a single dose or divided in several
doses.
[0063] The classic, first generation antipsychotics (neuroleptics)
like chlorpromazine act by direct blocking the D.sub.2 dopamine
receptors. They diminish positive symptoms of schizophrenia
(conceptual disorganization, delusions, hallucination) effectively
but not the negative ones (anhedonia, flat affect, social
withdrawal). By direct blocking of the nigrostriatal dopaminergic
pathways they induce extrapyramidal side effects.
[0064] The second generation "atypical" antipsychotics like
clozapine were introduced into clinical practice in an attempt to
enhance therapeutical efficacy (i.e. diminishing both positive and
negative symptoms) and to decrease the side effects. Their D.sub.2
antagonist character is weaker and they are antagonists of the
serotonin (5HT.sub.2A) receptors, too. Atypical antipsychotics have
reduced risk for extrapyramidal side effects, however, they are too
have some (e.g. agranulocytosis induced by clozapine.) Atypical
antipsychotics generally induce remarkable weight gain, increase
the risk for diabetes and raise cholesterol level. Possibly due to
the serotonergic antagonism, they may induce obsessive-compulsive
symptoms, too. Depression and anxiety as well as sleep disturbances
are common in psychotic patients, therefore, antipsychotics are
mostly not used as monotherapy.
[0065] Another aspect of the invention is directed to a composition
comprising the compounds of formula (I) (e.g. a pharmaceutical
composition). This composition may further include a carrier and/or
other additives (e.g. the composition may comprise a compound of
formula (I) acting as an active pharmaceutical ingredient and a
carrier).
[0066] The compounds of formula (I) can be formulated in a
pharmaceutically acceptable carrier including diluents, excipients,
fillers, binders, solvents, etc. (see Remington's Pharmaceutical
Sciences, 18.sup.th Ed., Gennaro, Mack Publishing Co., Easton, Pa.
1990 and Remington: The Science and Practice of Pharmacy,
Lippincott, Williams & Wilkins, 1995). While the type of
pharmaceutically acceptable carrier/vehicle employed in generating
the compositions of the invention will vary depending upon the mode
of administration of the composition to a human or other mammal,
generally pharmaceutically acceptable carriers are physiologically
inert and non-toxic. Formulations of pharmaceutical compositions
may contain more than one type of compound of formula (I), as well
as any other pharmacologically active ingredient useful for the
treatment of the particular conditions, disease, or symptom being
treated.
[0067] The compositions of the invention can be administered by
standard routes (e.g., oral, inhalation, rectal, nasal, topical,
including buccal and sublingual, or parenteral, including
subcutaneous, intramuscular, intravenous, intradermal, transdermal,
and intratracheal). In addition, polymers may be added according to
standard methodologies in the art for sustained release of a given
compound.
[0068] For oral administration, the compositions of the invention
may be presented as discrete units such as capsules, caplets,
gelcaps, cachets, pills, or tablets each containing a predetermined
amount of the active ingredient as a powder or granules; as a
solution or a suspension in an aqueous liquid or a non-aqueous
liquid; or as an oil-in-water liquid emulsion or a water-in-oil
emulsion and as a bolus, etc. Alternately, administration of a
composition including the compound of formula (I) may be effected
by liquid solutions, suspensions or elixirs, powders, lozenges,
micronized particles and osmotic delivery systems.
[0069] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain antioxidants, stabilizers, buffers, bacteriostats and
solutes which render the formulation isotonic with the blood of the
intended recipient; and aqueous and non-aqueous sterile suspensions
which may include suspending agents and thickening agents.
[0070] It will be appreciated by those of skill in the art that the
number of administrations of the compounds according to the
invention will vary from patient to patient based on the particular
medical status of that patient at any given time.
SYNTHETIC EXAMPLES
[0071] The compounds according to the invention and the process for
their preparation are illustrated in detail by the following
Examples.
[0072] The following examples are intended to further illustrate
certain preferred embodiments of the invention and are not limiting
in nature. Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific substances and procedures described
herein.
[0073] The novel starting materials of Examples were synthesized as
follows.
General Procedure for the Synthesis of 7,8-dimethoxy (or
dialkoxy)-4-methyl-1-(substituted)
phenyl-4,5-dihydro-3H-[2,3]benzodiazepine derivatives
[0074] Step 1
[0075] (S)-, (R)- or (R,S)-3,4-Dimethoxy-(or
dialkoxy)phenyl-isopropanol (10.0 mmol) and an equivalent amount of
a substituted benzaldehyde derivative were dissolved in 20 ml of
toluene, 0.8 ml of concentrated hydrochloric acid was added and the
mixture was stirred for 16 h. The toluene solution was decanted
from an oily residue which formed during the reaction and the
solvent was evaporated. The residue was triturated with ethanol to
give a solid which was then recrystallized from ethanol to give the
corresponding 6,7-dialkoxy-3-methyl-1-(substituted
phenyl)-isochromane derivative.
[0076] Step 2
[0077] Method A
[0078] To a stirred solution of the isochromane derivative of Step
1 in dichloromethane, containing 5% water, 1.5 equiv. of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added over 15 min.
Stirring was continued for 3 h, when TLC (eluent: hexane-ethyl
acetate) showed full conversion. The suspension was filtered and
the filtrate was washed several times with 1N sodium hydroxide
solution and water. Drying and evaporation gave the crude hemiketal
(a stereoisomeric mixture of
6,7-dialkoxy-1-hydroxy-3-methyl-1-(substituted phenyl)-isochromane
derivatives) that was used in Step 3.
[0079] Method B
[0080] The isochromane of Step 1 was dissolved in a tenfold amount
of an 8:7 mixture of dimethylformamide and dimethylsulfoxide. The
solution was cooled to 5-10.degree. C. and air, enriched with
oxygen up to 40%, was bubbled through the solution. Then a 50%
solution of sodium hydroxide in water (2.5 equiv.) was added and
stirring was continued for 5 h. The reaction mixture was then
poured onto a mixture of ice and water containing hydrochloric acid
in an equivalent amount with the previously applied sodium
hydroxide. The resulting suspension was aged by stirring for some
hours and filtered and the solid washed with water. The thus
prepared hemiketal was used without drying in the next step.
[0081] Step 3
[0082] To a solution of hemiketal (10.0 mmol) of Step 2 and 1.33
equiv. of tert-butyl carbazate in a tenfold amount of toluene, 0.12
ml of concentrated hydrochloric acid was added and the mixture was
heated to boiling with constant removal of water. After 3-4 h the
mixture was extracted with sodium hydrogen carbonate solution and
water. After drying and evaporation, a crude stereoisomeric mixture
of hydrazones corresponding to general formula (XI) was formed.
[0083] Step 4
[0084] To a solution of the hydrazone intermediate of Step 3 (ca.
10.0 mmol) in 45 ml of dichloromethane, 1.5 equivalents of
triethylamine were added and it was cooled to 0.degree. C. At this
temperature 1.2 equivalents of methanesulfonyl chloride were added
dropwise. When TLC (eluent: benzene-ethyl acetate (4:1)) showed
complete conversion, the mixture was extracted successively with
ice water, 1N hydrochloric acid and brine. Drying and evaporation
gave a foam which was dissolved in methanol and 1.2 equivalents of
a 50% sodium hydroxide solution in water was added drop-wise at
10.degree. C. Stirring was continued for 2-3 h at r.t., then the
solution was concentrated to 1/3 of its volume and water was added
to bring the precipitation to completion. After dilution of the
reaction mixture with water, sometimes extraction was necessary to
isolate the product of the ring closure. The obtained crude
7,8-dialkoxy-3-tert-butoxycarbonyl-4-methyl-4,5-dihydro-3H-[2,3]benzodiaz-
epine derivative was purified by recrystallization or by column
chromatography.
[0085] Step 5
[0086] The tert-butoxycarbonyl-2,3-benzodiazepine derivative of
Step 4 was added gradually at room temperature to a six-fold amount
of stirred ethyl acetate containing about 13% hydrochloric acid.
After 20 minutes generally a suspension formed which was stirred
for 3 h. The mixture was then diluted with ethyl acetate and
extracted with water, sodium hydrogen carbonate solution and brine.
After drying and evaporation the residue was recrystallized to give
the title compounds I-XVIII as follows (yields are overall yields).
[0087]
(R,S)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3]benzod-
iazepine (I), Mp.: 182-183.degree. C., yield: 46%. [0088]
(R)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3]benzodia-
zepine (II), Mp.: 171-172.degree. C., yield: 38%, [.alpha.]D:
+77.degree. (c=0.5, CHCl.sub.3). [0089]
(S)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3]benzodia-
zepine (III), Mp.: 168-170.degree. C., yield: 35%, [.alpha.].sub.D:
-76.degree. (c=0.5, CHCl.sub.3). [0090]
(R,S)-7,8-Dimethoxy-4-methyl-1-(2-nitrophenyl)-4,5-dihydro-3H-[2,3]benzod-
iazepine (IV), Mp.: 111-113.degree. C., yield: 52%. [0091]
(R,S)-7,8-Dimethoxy-4-methyl-1-(3-nitrophenyl)-4,5-dihydro-3H-[2,3]benzod-
iazepine (V), Mp.: 200-202.degree. C., yield: 54%. [0092]
(R)-7,8-Dimethoxy-4-methyl-1-(3-nitrophenyl)-4,5-dihydro-3H-[2,3]benzodia-
zepine (VI), Mp.: 187-188.degree. C., yield: 48%. [0093]
(R,S)-7,8-Dimethoxy-4-methyl-1-(3-methyl-4-nitrophenyl)-4,5-dihydro-3H-[2-
,3]benzodiazepine (VII), Mp.: 154-156.degree. C., yield: 54%.
[0094]
(R)-7,8-Dimethoxy-4-methyl-1-(3-methyl-4-nitrophenyl)-4,5-dihydro-3H-[2,3-
]benzodiazepine (VIII), Mp.: 151-152.degree. C., yield: 49%,
[.alpha.]D: +100.degree. (c=0.5, CHCl.sub.3). [0095]
(S)-7,8-Dimethoxy-4-methyl-1-(3-methyl-4-nitrophenyl)-4,5-dihydro-3H-[2,3-
]benzodiazepine (IX), Mp.: 148-150.degree. C., yield: 46%,
[.alpha.].sub.D: -99.degree. (c=0.5, CHCl.sub.3). [0096]
(R,S)-7,8-Dimethoxy-1-(3-chloro-4-nitrophenyl)-4-methyl-4,5-dihydro-3H-[2-
,3]benzodiazepine (X), Mp.: 156-158.degree. C., yield: 53%. [0097]
(R)-7,8-Dimethoxy-1-(3-chloro-4-nitrophenyl)-4-methyl-4,5-dihydro-3H-[2,3-
]benzodiazepine (XI), Mp.: 153-154.degree. C., yield: 53%,
[.alpha.].sub.D: -23.degree. (c=0.5, CHCl.sub.3). [0098]
(R)-1-(3,5-Dimethyl-4-nitrophenyl)-7,8-dimethoxy-4-methyl-4,5-dihydro-3H--
[2,3]benzodiazepine (XII), Mp.: 186-187.degree. C., yield: 43%,
[.alpha.].sub.D: +92.degree. (c=0.1, CHCl.sub.3). [0099]
(R,S)-7,8-Dimethoxy-1-(3-chlorophenyl)-4-methyl-4,5-dihydro-3H-[2,3]benzo-
diazepine (XIII), Mp.: 121-122.degree. C., yield: 51%. [0100]
(R,S)-7,8-Dimethoxy-1-(4-chlorophenyl)-4-methyl-4,5-dihydro-3H-[2,3]benzo-
diazepine (XIV), Mp.: 137-140.degree. C., yield: 56%. [0101]
(R,S)-7,8-Dimethoxy-1-(4-fluorophenyl)-4-methyl-4,5-dihydro-3H-[2,3]benzo-
diazepine (XV), Mp.: 136-137.degree. C., yield: 51%. [0102]
(R,S)-7,8-Dimethoxy-1-(3,4-dimethoxyphenyl)-4-methyl-4,5-dihydro-3H-[2,3]-
benzodiazepine (XVI), Mp.: 125-126.degree. C., yield: 55%. [0103]
(R,S)-7,8-Dimethoxy-4-methyl-1-phenyl-4,5-dihydro-3H-[2,3]benzodiazepine
(XVII), Mp.: 142-145.degree. C., yield: 51%. [0104]
(R,S)-7,8-Diethoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3]benzodi-
azepine (XVIII), Mp.: 137-138.degree. C., yield: 62%.
(R,S)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-3-thiocarbamoyl-4,5-dihydro-
-3H-[2,3]benzodiazepine (XIX)
[0105] A mixture of compound I (2.0 g, 5.86 mmol) and 0.85 (8.75
mmol) potassium thiocyanate in 40 ml of acetic acid was heated at
110.degree. C. for 6 h. After cooling the separated crystals were
filtered and washed with water and dried to give 1.94 g (83%) of
the title compound. Mp.: 246-247.degree. C.
[0106] Compounds XX-XXIV were synthesized similarly to compound
XIX. (Occasionally no spontaneous precipitate forming occurred
during cooling. In such instances, water was added to the reaction
mixture until crystallization began.)
TABLE-US-00001 ##STR00013## Configuration Yield (%) No. at C-4
R.sup.1 R.sup.2 Mp (.degree. C.) [.alpha.].sub.D XX R H NO.sub.2
242-243 77 -192.degree. (c = 0.3, CHCl.sub.3) XXI R,S CH.sub.3
NO.sub.2 209-211 63 XXII R CH.sub.3 NO.sub.2 195-197 83
-178.degree. (c = 0.5, CHCl.sub.3) XXIII R Cl NO.sub.2 197-198 80
-156.degree. (c = 0.5, CHCl.sub.3) XXIV R,S Cl H 179-180 76
(R,S)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3]benzodi-
azepine-3-carbothioyl chloride (XXV)
[0107] A solution of 3.41 g (10.0 mmol) of compound I and ml (15.5
mmol) triethylamine in 180 ml of benzene was added drop-wise to a
stirred solution of 1.38 g (12.0 mmol) of thiophosgene in 30 ml of
benzene. After stirring at r.t. for 16 h the reaction mixture was
quenched with water (30 ml). After separation the organic phase was
extracted with water (2.times.30 ml) and brine. After drying and
evaporation the residue was triturated with diisopropyl ether to
give 3.75 g (89%) of the solid title compound. Mp.: 165-167.degree.
C.
[0108] Compounds XXVI-XXXV were prepared in a similar fashion:
TABLE-US-00002 ##STR00014## Configu- ration Mp Yield (%) No. at C-4
R.sup.1 R.sup.2 R.sup.3 (.degree. C.) [.alpha.].sub.D XXVI R H
NO.sub.2 CH.sub.3 159-162 82 -653.degree. (c = 0.5, CHCl.sub.3)
XXVII S H NO.sub.2 CH.sub.3 156-158 83 +588.degree. (c = 0.5,
CHCl.sub.3) XXVIII R,S CH.sub.3 NO.sub.2 CH.sub.3 174-176 85 XXIX R
CH.sub.3 NO.sub.2 CH.sub.3 168-170 89 -488.degree. (c = 0.5,
CHCl.sub.3) XXX R,S Cl NO.sub.2 CH.sub.3 155-157 84 XXXI R Cl
NO.sub.2 CH.sub.3 151-153 87 -526.degree. (c = 0.5, CHCl.sub.3)
XXXII R,S Cl H CH.sub.3 77-78 79 XXXIII R,S H Cl CH.sub.3 177-178
81 XXXIV R,S CH.sub.3O CH.sub.3O CH.sub.3 205-206 74 XXXV R,S H
NO.sub.2 CH.sub.3CH.sub.2 95-98 82
(R,S)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3]benzodi-
azepine-3-carbonitrile (XXXVI)
[0109] A mixture of compound I (3.41 g, 10.0 mmol), 1.38 g (10.0
mmol) of dry potassium carbonate and 1.80 g (17.0 mmol) of cyanogen
bromide in 50 ml of dimethylformamide was stirred at r.t. for 20 h.
The reaction mixture was poured onto water and the precipitate was
filtered and washed with water. After drying the title substance
weighed 3.45 g (94%). Mp.: 208-211.degree. C.
[0110] Similarly, were prepared the following compounds were
prepared (starting materials) XXXVII-XLVI:
TABLE-US-00003 ##STR00015## Configu- ration Mp Yield (%) No. at C-4
R.sup.1 R.sup.2 R.sup.3 (.degree. C.) [.alpha.].sub.D XXXVII R H
NO.sub.2 CH.sub.3 187-189 92 +46.degree. (c = 0.3, CHCl.sub.3
XXXVIII R,S CH.sub.3 NO.sub.2 CH.sub.3 180-182 94 XXXIX R CH.sub.3
NO.sub.2 CH.sub.3 167-169 95 +37.degree. (c = 0.2, CHCl.sub.3 XL S
CH.sub.3 NO.sub.2 CH.sub.3 175-176 84 -41.degree. (c = 0.3,
CHCl.sub.3 XLI R,S Cl NO.sub.2 CH.sub.3 160-162 89 XLII R Cl
NO.sub.2 CH.sub.3 150-155 91 +21.degree. (c = 0.5, CHCl.sub.3 XLIII
R,S H Cl CH.sub.3 179-180 81 XLIV R,S H F CH.sub.3 155-156 81 XLV
R,S CH.sub.3O CH.sub.3O CH.sub.3 197-198 78 XLVI R,S H NO.sub.2
CH.sub.3CH.sub.2 131-132 82
Examples 1-11
General Procedure for the Synthesis of
7,8-dimethoxy-4-methyl-1-(substituted)
phenyl-3-(thiazol-2-yl)-4,5-dihydro-3H-[2,3]benzodiazepines
[0111] A 7,8-dimethoxy-4-methyl-1-(substituted)
phenyl-3-thiocarbamoyl-4,5-dihydro-3H-[2,3]benzodiazepine
derivative (selected from corresponding compounds XIX-XXIV) (3.00
mmol) was reacted with a two- to four fold excess of an
.alpha.-haloaldehyde acetal derivative (bromoacetaldehyde diethyl
acetal, 2-bromopropionaldehyde dimethyl acetal) or alternatively
with an .alpha.-haloketone (chloroacetone, 3-chlorobutanone) in
dimethylformamide (12-15 ml) at 80.degree. C. (with the
haloaldehyde acetals) or at 40-70.degree. C. (with the haloketones)
for 1.5-4 h. Dilution with water resulted in a precipitate which
was purified either by recrystallization or column chromatography
using silica gel and a (1:1) solvent mixture of hexane and ethyl
acetate as eluent or by boiling a suspension of the crude product
in ethanol.
[0112] The following compounds were prepared by this procedure:
TABLE-US-00004 ##STR00016## Configu- No. of ration Mp Yield (%)
Example at C-4 R.sup.1 R.sup.2 R.sup.3 R.sup.4 (.degree. C.)
[.alpha.].sub.D 1 R,S H H H NO.sub.2 195-197 75 2 R H H H NO.sub.2
151-152 74 +663.degree. (c = 0.5, CHCl.sub.3 3 R,S H H CH.sub.3
NO.sub.2 145-147 79 4 R H H CH.sub.3 NO.sub.2 172-174 73
+578.degree. (c = 0.5, CHCl.sub.3 5 R H H Cl NO.sub.2 168-169 76
+766.degree. (c = 0.5, CHCl.sub.3 6 R,S CH.sub.3 H H NO.sub.2
194-195 87 7 R,S H CH.sub.3 H NO.sub.2 122-123 90 8 R,S CH.sub.3
CH.sub.3 H NO.sub.2 192-193 96 9 R CH.sub.3 CH.sub.3 H NO.sub.2
190-192 84 +414.degree. (c = 0.2, CHCl.sub.3 10 R,S H H Cl H
125-126 75 11 R,S CH.sub.3 CH.sub.3 Cl H 174-176 78 (HCl salt)
Example 12
(R,S)-3-(4,5-Dihydro-thiazol-2-yl)-7,8-dimethoxy-4-methyl-1-(4-nitrophenyl-
)-4,5-dihydro-2H-[2,3]benzodiazepine
[0113] Starting compound XIX (1.00 g, 2.45 mmol) was heated with
1.20 g (5.86 mmol) of 2-bromoethylamine hydrobromide in 20 ml of
dimethylformamide at 70.degree. C. for 12 h. After dilution with
water the precipitate was filtered and recrystallized from ethanol
to give 0.83 g (79%) of title compound. Mp.: 220-222.degree. C.
Example 13
(R)-3-(4,5-Dihydro-thiazol-2-yl)-7,8-dimethoxy-4-methyl-1-(4-nitrophenyl)--
4,5-dihydro-2H-[2,3]benzodiazepine
[0114] Starting compound XX was reacted as in Example 13 to form
the title compound.
[0115] Yield: 79%, mp.: 206-212.degree. C. [.alpha.].sub.D:
+714.degree. (c=0.2, CHCl.sub.3)
Example 14
(R,S)-3-(4,5-Dihydro-4-oxo-thiazol-2-yl)-7,8-dimethoxy-4-methyl-1-(4-nitro-
phenyl)-4,5-dihydro-2H-[2,3]benzodiazepine
[0116] Starting compound XIX (0.50 g, 1.25 mmol) was reacted with
0.38 g (2.48 mmol) of methyl-2-bromoacetate in 14 ml of
dimethylformamide at 50.degree. C. for 2 h. The reaction mixture
was diluted with water and the precipitate formed was filtered and
dried. Purification of this product was done by stirring and
heating an ethanolic suspension for 15 min at boiling temperature.
Filtration gave the title compound (0.52 g, 94%), mp.:
238-239.degree. C.
Example 15
(R,S)-3-(4,5-Dihydro-5-methyl-4-oxo-thiazol-2-yl)-7,8-dimethoxy-4-methyl-1-
-(4-nitrophenyl)-4,5-dihydro-2H-[2,3]benzodiazepine
[0117] The title compound was prepared as in example 14, but with
ethyl-2-bromopropionate as a reagent.
[0118] Yield: 92%, mp.: 213-214.degree. C.
Examples 16-28
General Procedure for Synthesis of
7,8-dialkoxy-4-methyl-1-(substituted)
phenyl-3-(1,3,4-thiadiazol-2-yl)-4,5-dihydro-3H-[2,3]benzodiazepines
[0119] A 4,5-dihydro-3H-[2,3]benzodiazepine-3-carbothioyl chloride
derivative (one of starting compounds XXV-XXXV) (8.1 mmol) was
added gradually to a vigorously stirred mixture of 1.21 g (24.2
mmol) of 98% hydrazine hydrate in tetrahydrofuran (72 ml) at
5-10.degree. C. After 1 h stirring at r.t., the solvent was
evaporated and the residue triturated with water. The precipitate
was filtered and dried. The thus prepared intermediate
4,5-dihydro-3H-[2,3]benzodiazepine-3-carbothiohydrazide derivative
was heated in 30 ml of triethyl orthoformate at 100.degree. C. for
2 h. After cooling a precipitate formed which was filtered and
washed with ethanol to give the title products with a
non-substituted 1,3,4-thiadiazole ring as substituent.
[0120] Alternatively, in the examples in which a 5'-methyl or ethyl
substituted 3-(1,3,4-thiadiazol-2-yl)benzodiazepine was formed, the
intermediate 3-carbothiohydrazide derivative was first reacted at
r.t. with 1.2 equiv. of acetylchloride in dichloromethane in the
presence of triethylamine or was reacted with 1.5 equiv. of
propionic anhydride at r.t. for 3 h and then p-toluenesulfonic acid
hydrate (1.5 equiv) was added and the mixture was stirred for 16 h.
After dilution with dichloromethane the solution was extracted
successively with water, sodium hydrogencarbonate and water. The
organic phase was dried and the solvent evaporated to give the
title product, which was purified by recrystallization from
ethanol.
[0121] The following compounds were prepared according to this
procedure:
TABLE-US-00005 ##STR00017## No. of Ex- Config- am- uration Mp Yield
(%) ple at C-4 R.sup.1 R.sup.2 R.sup.3 R.sup.4 (.degree. C.)
[.alpha.].sub.D 16 R,S H H NO.sub.2 CH.sub.3 210-212 74 17 R H H
NO.sub.2 CH.sub.3 224-225 66 +610.degree. (c = 0.5, CHCl.sub.3) 18
S H H NO.sub.2 CH.sub.3 229-231 68 -549.degree. (c = 0.5,
CHCl.sub.3) 19 R,S H CH.sub.3 NO.sub.2 CH.sub.3 195-196 80 20 R H
CH.sub.3 NO.sub.2 CH.sub.3 192-195 74 +429.degree. (c = 0.1,
CHCl.sub.3) 21 R,S H Cl NO.sub.2 CH.sub.3 214-215 71 22 R H Cl
NO.sub.2 CH.sub.3 203-206 67 +613.degree. (c = 0.3, CHCl.sub.3) 23
R,S H Cl H CH.sub.3 86-88 65 24 R,S H H Cl CH.sub.3 203-204 68 25
R,S H CH.sub.3O CH.sub.3O CH.sub.3 173-174 59 26 R,S H H NO.sub.2
CH.sub.3CH.sub.2 172-174 68 27 R,S CH.sub.3 H NO.sub.2 CH.sub.3
228-229 84 28 R CH.sub.3 H NO.sub.2 CH.sub.3 203-204 85
CH.sub.2
Examples 29, 30
General Procedure for the Synthesis of
7,8-dimethoxy-4-methyl-1-(4-nitrophenyl)-3-(1,3,4-oxadiazol-2-yl)-4,5-dih-
ydro-3H-[2,3]benzodiazepines
[0122] Step 1
[0123] To a solution of starting compound XXV (0.78 g, 1.86 mmol),
0.26 ml (1.87 mmol) of triethylamine and a catalytic amount of
4-dimethylaminopyridine in 10 ml of dimethylformamide formic
hydrazide (or acethydrazide) (18.6 mmol) dissolved in
dimethylformamide (10 ml) was added drop-wise. The reaction mixture
was stirred at r.t. for 70 h, then diluted with water and the
precipitate was filtered. This intermediate was purified by column
chromatography (silica gel, eluent: hexane-ethyl acetate
(1:2)).
[0124] Step 2
[0125] The intermediate of Step 1 was dissolved in ethanol (10 ml)
and after the addition of mercury (II) acetate (0.38 g, 1.19 mmol)
the mixture was stirred and heated to a boil for 2 h. After
evaporation of the solvent the residue was taken up with
dichloromethane and filtered through a pad of neutral aluminium
oxide. The solution was evaporated to dryness and the residue was
purified by column chromatography (silica gel, eluent: hexane-ethyl
acetate (2:3)).
[0126] The following compounds were prepared by this procedure:
TABLE-US-00006 ##STR00018## No. of Configuration Example at C-4 R
Mp (.degree. C.) Yield (%) 29 R,S H 225-229 33 30 R,S CH.sub.3
177-178 41
Example 31
(R,S)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-3-(5-oxo-5,6-dihydro-4H-[1,-
3,4]thiadiazin-2-yl)-4,5-dihydro-3H-[2,3]benzodiazepine
[0127] Starting compound XXV was transformed into the corresponding
3-carbothiohydrazide intermediate according to the general
procedure described for Examples 16-28. A mixture of this
intermediate (0.83 g, 2.0 mmol), 0.34 g (2.46 mmol) of dry
potassium carbonate and 0.20 ml (2.45 mmol) of chloroacetyl
chloride in 10 ml of dimethylformamide was then stirred for 24 h.
The reaction mixture was quenched with a five-fold amount of water
and the precipitate was filtered, washed with water and dried. The
crude product was purified by column chromatography using ethyl
acetate-hexane (1:1) as an eluent. The title substance weighed 0.57
g (62%), mp.: 229-231.degree. C.
Examples 32-37
General Procedure for Synthesis of
7,8-dimethoxy-4-methyl-1-(substituted)
phenyl-3-(1,4,2-oxathiazol-3-yl)-4,5-dihydro-3H-[2,3]benzodiazepines
[0128] The corresponding starting compound carbothioyl chloride
from the group of XXV-XXXV (3.86 mmol) was added gradually over 15
min to a stirred and cooled (0-5.degree. C.) mixture of 0.82 g
(11.8 mmol) hydroxylamine hydrochloride and 0.49 g (12.25 mmol)
sodium hydroxide in 23 ml of ethanol. Stirring was continued at
r.t. for 20 h and after dilution with water the precipitate was
filtered and dried. This intermediate thiohydroxamic acid was
dissolved in acetone and potassium carbonate (0.69 g, 4.99 mmol)
was added. To this suspension a solution of diiodomethane (1.1 g,
4.11 mmol) in 5 ml of acetone was added drop-wise and stirring was
continued for 24 h. The reaction mixture was diluted with water and
extracted with ethyl acetate. Evaporation gave the crude product
which was purified by column chromatography (silica gel, eluent:
hexane-ethyl:acetate (1:1)).
[0129] The following compounds were prepared according to the above
procedure:
TABLE-US-00007 ##STR00019## No. of Configuration Yield (%) Example
at C-4 R.sup.1 R.sup.2 Mp (.degree. C) [.alpha.].sub.D 32 R,S H
NO.sub.2 195-198 38 33 R H NO.sub.2 206-208 31 +604.degree. (c =
0.5, CHCl.sub.3) 34 S H NO.sub.2 209-211 36 -551.degree. (c = 0.5,
CHCl.sub.3) 35 R CH.sub.3 NO.sub.2 180-182 35 +429.degree. (c =
0.1, CHCl.sub.3) 36 R,S H F 186-191 43 37 R,S H H 170-173 38
Example 38
(R,S)-Dimethoxy-4-methyl-3-(2-methyl-3-oxo-2,3-dihydro-1,2,4-thiadiazol-5--
yl)-1-(4-nitrophenyl)-4,5-dihydro-[2,3]benzodiazepine
[0130] Step 1
[0131] To a solution of 0.37 g (3.80 mmol) of potassium thiocyanate
in 8 ml of acetone, phenyl chloroformate (0.48 ml, 3.80 mmol) was
added drop-wise at r.t. Stirring was continued at r.t. for 30 min
and then it was heated to 40.degree. C. for 15 min. This solution
was cooled with ice-water and a solution of the starting compound I
(1.09 g, 3.19 mmol) in acetone (15 ml) was added drop-wise.
Stirring was continued at r.t. for 20 h and the mixture was poured
onto water. The 3-(phenoxycarbonyl-thiocarbamoyl)-benzodiazepine
intermediate separated as a precipitate, which was filtered, washed
and dried to give a solid with mp.: 107-110.degree. C.
[0132] Step 2
[0133] This solid intermediate was dissolved in 10 ml of
dimethylformamide and a methylamine solution in water (40%, 0.35
ml, 4.04 mmol) was added drop-wise. After 3 h of stirring, the
mixture was diluted with water and the precipitate formed was
isolated by suction, washed and dried. The thus formed
intermediate:
(R,S)-1-methyl-3-[7,8-dimethoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-
-[2,3]benzodiazepine-3-carbothioyl]-urea (mp.: 197-199.degree. C.)
was used in the next ring-closure step.
[0134] Step 3
[0135] The compound prepared in Step 2 (1.01 g, 2.21 mmol) was
dissolved in chloroform (20 ml) and a solution of bromine (0.42 g,
2.63 mmol) in chloroform (6 ml) was added drop-wise. After 1 h, the
solution was diluted with 30 ml of chloroform and extracted
successively with sodium bicarbonate solution and water. After
drying and evaporation the remaining crude title product was
purified by column chromatography on silica gel applying a 95:5
mixture of ethyl acetate as an eluent. Evaporation of the main
fraction gave the title product: 0.75 g (56% overall). Mp.:
262-263.degree. C.
Example 39
(R,S)-7,8-Dimethoxy-3-(4,5-dihydro-oxazol-2-yl)-4-methyl-1-(4-nitrophenyl)-
-4,5-dihydro-3H-[2,3]benzodiazepine
[0136] Starting substance I (1.50 g, 4.39 mmol) was reacted with
2-chloroethyl isocyanate (0.93 g, 8.82 mmol) in dichloromethane (30
ml) for 24 h at r.t. After evaporation the residue washed with
hexane and dissolved in 30 ml of dimethylformamide. Dry potassium
carbonate (0.69 g, 4.99 mmol) and potassium iodide (0.40 g, 2.41
mmol) were added and the mixture was heated at 100-110.degree. C.
for 6 h. Dilution with water gave a solid which was purified by
column chromatography on silica gel using a 95:5 mixture of ethyl
acetate and methanol as eluent to give 0.62 g (34%) of the title
product as a solid foam.
Examples 40-53
General Procedure for Synthesis of
7,8-dialkoxy-4-methyl-1-(substituted)
phenyl-3-(1,2,4-oxadiazol-3-yl)-4,5
dihydro-3H-[2,3]benzodiazepines
[0137] To a solution of a benzodiazepine-3-carbonitrile derivative
from starting compounds XXXVI-XLVI (11.05 mmol) in tetrahydrofuran
1.60 g (19.5 mmol) of sodium acetate and 0.95 g (13.67 mmol) of
hydroxylamine hydrochloride was added and the mixture was stirred
at r.t. for 5 h. The solvent was evaporated and the residue treated
with water gave the corresponding amidoxime intermediate which was
isolated by filtration. After drying this intermediate was taken up
in triethyl orthoformate (40 ml), catalytic amount of concentrated
hydrochloric acid was added and the mixture was stirred and heated
for 1 h at 110.degree. C. (Alternatively, acetic anhydride (10-15
ml) was used instead of triethyl orthoformate for the synthesis of
(5-methyl-1,2,4-oxadiazol-3-yl) substituted benzodiazepines.) After
cooling, title products usually crystallized out of the reaction
mixture or the reaction mixture was concentrated and the residue
was treated with water, then the product was extracted with ethyl
acetate. Crude products were purified by heating their ethanolic
suspensions to boiling and after cooling the crystals were filtered
off.
[0138] The following compounds were prepared by the above
procedure:
TABLE-US-00008 ##STR00020## No. of Ex- Config- am- uration Mp Yield
(%) ple at C-4 R.sup.1 R.sup.2 R.sup.3 R.sup.4 (.degree. C.)
[.alpha.].sub.D 40 R,S H H NO.sub.2 CH.sub.3 213-214 72 41 R H H
NO.sub.2 CH.sub.3 190-192 65 -409.degree. (c = 0.5, CHCl.sub.3) 42
R,S H CH.sub.3 NO.sub.2 CH.sub.3 229-230 88 43 R H CH.sub.3
NO.sub.2 CH.sub.3 223-225 79 -483.degree. (c = 0.3, CHCl.sub.3) 44
S H CH.sub.3 NO.sub.2 CH.sub.3 216-218 69 +452.degree. (c = 0.2,
CHCl.sub.3) 45 R,S H Cl NO.sub.2 CH.sub.3 227-230 71 46 R H Cl
NO.sub.2 CH.sub.3 206-208 70 -421.degree. (c = 0.25, CHCl.sub.3) 47
R CH.sub.3 CH.sub.3 NO.sub.2 CH.sub.3 206-208 65 -456.degree. (c =
0.4, CHCl.sub.3) 48 R,S CH.sub.3 H NO.sub.2 CH.sub.3 197-199 63 49
R,S H H Cl CH.sub.3 210-212 70 50 R,S H H F CH.sub.3 217-220 79 51
R,S H H H CH.sub.3 215-216 78 52 R,S H H NO.sub.2 CH.sub.3CH.sub.2
158-162 48 53 R,S H CH.sub.3O CH.sub.3O CH.sub.3 188-189 69
Example 54
(R)-7,8-Dimethoxy-4-methyl-1-(3-methyl-4-nitrophenyl)-3-(5-oxo-4H-1,2,4-ox-
adiazol-3-yl)-4,5-dihydro-3H-[2,3]benzodiazepine
[0139] Starting compound XXXIX (1.60 g, 4.21 mmol) was transformed
into the amidoxime intermediate according to the general procedure
described for Examples 40-53. This intermediate (1.38 g, 3.34 mmol)
was dissolved in 60 ml of dichloromethane and reacted with 0.59 g
(3.64 mmol) of 1,1'-carbonyldiimidazole at 40.degree. C. for 10 h.
The reaction mixture was diluted with dichloromethane (60 ml),
extracted successively with 0.25N hydrochloric acid and water.
After drying and evaporation the crude title product was
recrystallized from ethanol to give 1.26 g (68%). Mp.:
221-223.degree. C. [.alpha.].sub.D: +242.degree. (c=1.5,
CHCl.sub.3).
Examples 55-60
General Procedure for Synthesis of
7,8-dimethoxy-4-methyl-1-(4-nitrophenyl)-3-[1H(2H)-1,2,4-triazol-3-yl]-4,-
5-dihydro-3H-[2,3]benzodiazepines
[0140] Step 1
[0141] Starting compound XIX was reacted in dimethylformamide at
r.t. with an equivalent amount of methyl iodide in the presence of
potassium carbonate to give
(R,S)-7,8-dimethoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3]benzod-
iazepine-3-S-methyl-thiocarboximidate. Mp.: 153-155.degree. C.
[0142] Step 2
[0143] The compound prepared in Step 1 (0.82 g, 1.98 mmol) was
heated in 2-methoxyethanol (30 ml) with formic hydrazide or
acethydrazide (19.98 mmol) and a catalytic amount of
p-toluenesulfonic acid at 100-110.degree. C. for 5 h. After
evaporation the residue was triturated with water to give the crude
product which was purified by column chromatography on silica gel
with hexane-ethyl acetate (1:2) as an eluent.
[0144] Step 3 (Optional)
[0145] N-methylated derivatives of the title compounds were
prepared from compounds obtained in Step 2 by reacting the latter
with methyl iodide in tetrahydrofuran in the presence of equivalent
amount of tert-butoxide at r.t. for 16 h. Then the reaction mixture
was diluted with water and the products were extracted with ethyl
acetate. Two products formed in each of the reactions,
corresponding to the tautomeric possibilities, which were separated
by column chromatography on silica gel using ethyl acetate as an
eluent.
[0146] The following compounds were prepared (yields are
overall)
TABLE-US-00009 ##STR00021## No. of Configuration Example at C-4
R.sup.1 R.sup.2 Mp (.degree. C.) Yield (%) 55 R,S H H 244-246 39 56
R,S H CH.sub.3 237-239 56 57 R,S 1-CH.sub.3 H 132-136 23 58 R,S
2-CH.sub.3 H 98-100 24 59 R,S 1-CH.sub.3 CH.sub.3 250-252 19 60 R,S
2-CH.sub.3 CH.sub.3 79-81 17
Example 61
(R,S)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-3-(5-methyloxazol-2-yl)-4,5-
-dihydro-3H-[2,3]benzodiazepine
[0147] A solution of the compound of Example 63 (3.2 g, 7.35 mmol)
and 8.10 g (69.2 mmol) C-(2-methyl-[1,3]dioxolan-2-yl)-methylamine
in 200 ml of 1,2-dichloroethane was stored at r.t. for 36 h. The
solution was then washed with water (3.times.100 ml), dried and
evaporated to dryness. The thus prepared solid was recrystallized
from ethanol to give 2.95 g (83%, mp.: 139.140.degree. C.) of the
intermediate
(R,S)-7,8-dimethoxy-3-[N'-(2,2-ethylenedioxy-1-propyl)-carbamoyl]-4-methy-
l-1-(4-nitrophenyl)-4,5-dihydro-[2,3]benzodiazepine.
[0148] Of the above intermediate 2.50 g (5.16 mmol) were added
gradually to 40 ml of methanesulfonic acid at r.t., followed by the
addition of 4.00 g (14.1 mmol) of phosphorous pentoxide. This
reaction mixture was kept at r.t. for 9 days and then it was
quenched carefully with 400 ml of ice-water and neutralized with
potassium carbonate. A solid was separated which was dissolved in
dichloromethane. This solution was washed with water, dried and
evaporated to dryness. The thus prepared crude title product was
recrystallized from methanol to give 0.71 g (36%) of the product
with mp.: 161-166.degree. C.
Example 62
(R)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-3-(2-pyridyl)-4,5-dihydro-3H--
[2,3]benzodiazepine
[0149] Step 1
[0150]
(3S)-6,7-Dimethoxy-1-hydroxy-3-methyl-1-(4-nitrophenyl)-isochromane
(2.40 g, 9.65 mmol; product of Step 2 of general procedure for
Starting compound II) and 2-hydrazinopyridine (0.91 g, 8.34 mmol)
were dissolved in toluene (30 ml) and after the addition of 0.20 ml
of concentrated hydrochloric acid the mixture was heated under
reflux with continuous removal of water. After 3 h the mixture was
extracted with sodium carbonate solution and water and the solvent
was evaporated to give a solid, which was recrystallized from
ethanol to give the hydrazone intermediate: 1.54 g (3.54 mmol),
mp.: 233-234.degree. C.
[0151] Step 2
[0152] To a solution of the above hydrazone intermediate in 60 ml
of dichloromethane 0.96 ml (6.19 mmol) of triethylamine was added.
The solution was cooled to 0.degree. C. Methanesulfonyl chloride
(0.45 ml, 5.70 mmol) was added drop-wise and the mixture was
stirred at 0-5.degree. C. for 2 h. The reaction mixture was then
extracted successively with ice-water, 1N hydrochloric acid and
brine and it was concentrated to a volume of about 7 ml. To this
mixture 6 ml of methanol were added and a 50% sodium hydroxide
solution in water (prepared from 0.20 g (5.0 mmol) of sodium
hydroxide and 0.20 ml of water) was added dropwise at ca 10.degree.
C. Stirring was continued for 3 h at r.t., then the solution was
evaporated to 1/3 of its volume and 30 ml of water was added
gradually over 30 min. Crystals separated which were filtered and
washed with water. The crude product was recrystallized after
drying from 7.2 ml of 2-methoxyethanol to give 1.14 g (28%) of the
title product with mp.: 210-214.degree. C.
Example 63
(R,S)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-3-phenoxycarbonyl-4,5-dihyd-
ro-3H-[2,3]benzodiazepine
[0153] To a solution of starting compound I (3.41 g, 10.0 mmol) in
100 ml of dichloromethane 2.75 ml (20.0 mmol) of triethylamine and
3.13 g (20.0 mmol) of phenyl chloroformate was added and the
reaction mixture was kept at r.t. for 24 h. After evaporation of
the solvent, the residue was triturated with 60 ml of a 10% sodium
hydrogen carbonate solution in water and the precipitate was
filtered. After drying, the substance was suspended and heated to
boiling in diisopropyl ether for 30 min and filtered while hot. The
title compound weighed 4.12 g (89%). Mp.: 201-203.degree. C.
Example 64
(R,S)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3]benzodi-
azepine-3-carboxylic acid imidazolide
[0154] Starting compound I (3.41 g, 10.0 mmol) was reacted in 75 ml
of tetrahydrofuran with 1.95 g (12.0 mmol) of
1,1'-carbonyldiimidazole for 30 min at boiling temperature. The
reaction mixture was evaporated to dryness and the residue was
recrystallized from ethanol to give 3.71 g (85%) of the title
compound. Mp.: 164-165.degree. C.
Example 65
(R)-7,8-Dimethoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3]benzodiaz-
epine-3-carboxylic acid imidazolide
[0155] The title compound was prepared as described in example 64,
using the appropriate starting compound. Mp.: 161-162.degree. C.,
yield: 81%; [.alpha.].sub.D: -380.degree. (c=0.5, CHCl.sub.3).
Example 66
(R)-7,8-Dimethoxy-4-methyl-1-(3-methyl-4-nitrophenyl)-4,5-dihydro-3H-[2,3]-
benzodiazepine-3-carboxylic acid imidazolide
[0156] The title compound was prepared as described in example 64,
using the appropriate starting compound. Mp.: 167-169.degree. C.,
yield: 85%; [.alpha.].sub.D: -379.degree. (c=0.3, CHCl.sub.3).
Examples 67-101
General Procedures for Synthesis of 3-carbamoyl-1-(substituted)
phenyl-4,5-dihydro-3H-[2,3]benzodiazepines
[0157] The compounds of examples 67-101 were prepared using one of
the 5 methods below.
[0158] Method A
[0159] A 3-unsubstituted dihydro-benzodiazepine from the group of
starting materials I-XVIII (1.99 mmol) was reacted in
dichloromethane (10 ml) with an excess of an alkyl isocyanate
(12.09 mmol) at r.t. for 48 h. After evaporation the residue was
triturated with water and the precipitate was filtered and washed
with water. The crude substance was purified by recrystallization
from ethanol or column chromatography (silica gel, eluent:
hexane-ethyl acetate (1:1)).
[0160] Method B
[0161] A mixture of 1.99 mmol of a starting compound from the group
I-XVIII, 0.28 g (0.24 mmol) of potassium carbonate and 1.29 g (12.0
mmol) of dimethylcarbamoyl chloride was stirred at r.t. for 30 h.
The residue after evaporation was triturated with water and the
solid was filtered. The crude product was purified by column
chromatography on silica gel using hexane-ethyl acetate (1:1) as an
eluent.
[0162] Method C
[0163] The compound of example 63 (0.90 g, 1.95 mmol) was reacted
in dimethylformamide (23 ml) with about a tenfold excess of a
secondary or primary amine at 90-120.degree. C. for 4-7 h. The
reaction mixture was poured onto water and the solid product formed
was isolated by filtration. If necessary the product was
recrystallized.
[0164] Method D
[0165] A compound of Examples 64-66 (1.0 mmol) was reacted in
tetrahydrofuran or ethanol (15 ml) in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mmol) with the
corresponding alkylamine (8.5-20 mmol) by heating at reflux
temperature for 3-6 h. The reaction mixture was then concentrated
to dryness and the residue was taken up with water. The filtered
and dried product was recrystallized from ethanol or purified by
column chromatography on silica gel using hexane-ethylacetate
mixtures as eluent.
[0166] Method E
[0167] To a stirred mixture of O-methylhydroxylamine hydrochloride
g, 13.17 mmol) in dimethylsulfoxide (55 ml)
1.8-diazabicyclo[5,4,0]undec-7-ene (2.75 g, 18.06 mmol) was added
and stirring was continued for 0-5 h. To this solution 2.53 mmol of
a compound of examples 64 or 65 was added and the reaction was
stored at r.t. for 24 h. After dilution with water the mixture was
extracted with ethyl acetate and evaporation of the extract gave
the product which was purified by column chromatography on silica
gel using hexane-ethyl acetate (1:1) as eluent.
[0168] The following compounds were prepared by the above
procedures:
TABLE-US-00010 ##STR00022## Configura- Method No. of tion at of
Yield (%) Example C-4 synthesis R.sup.1 R.sup.2 R.sup.3 R.sup.4
R.sup.5 R.sup.6 Mp (.degree. C.) [.alpha.].sub.D 67 R,S A,D
CH.sub.3NH H H NO.sub.2 H CH.sub.3 196-197 74 68 R,S A CH.sub.3NH
NO.sub.2 H H H CH.sub.3 174-176 76 69 R,S A CH.sub.3NH H NO.sub.2 H
H CH.sub.3 83-85 74 70 R A,D CH.sub.3NH H H NO.sub.2 H CH.sub.3
134-135 76 +320.degree. (c = 0.5, CHCl.sub.3) 71 S A CH.sub.3NH H H
NO.sub.2 H CH.sub.3 117-123 83 -325.degree. (c = 0.2, CHCl.sub.3)
72 R,S A,D CH.sub.3NH H CH.sub.3 NO.sub.2 H CH.sub.3 194-195 88 73
R A CH.sub.3NH H CH.sub.3 NO.sub.2 H CH.sub.3 177-179 81
+339.degree. (c = 0.5, CHCl.sub.3) 74 S A CH.sub.3NH H CH.sub.3
NO.sub.2 H CH.sub.3 177-178 75 -344.degree. (c = 0.5, CHCl.sub.3)
75 R,S A CH.sub.3NH H Cl NO.sub.2 H CH.sub.3 194-195 85 76 R A
CH.sub.3NH H Cl NO.sub.2 H CH.sub.3 195-197 79 +360.degree. (c =
0.5, CHCl.sub.3) 77 R A CH.sub.3NH H CH.sub.3 NO.sub.2 CH.sub.3
CH.sub.3 158-160 87 +249.degree. (c = 0.3, CHCl.sub.3) 78 R,S A
CH.sub.3CH.sub.2NH H H NO.sub.2 H CH.sub.3 206-208 88 79 R A
CH.sub.3CH.sub.2NH H H NO.sub.2 H CH.sub.3 186-189 69 +400.degree.
(c = 0.5, CHCl.sub.3) 80 R A CH.sub.3CH.sub.2NH H CH.sub.3 NO.sub.2
H CH.sub.3 149-150 74 +369.degree. (c = 0.3, CHCl.sub.3) 81 R,S A
(CH.sub.3).sub.2CHNH H H NO.sub.2 H CH.sub.3 177-178 90 82 R A
(CH.sub.3).sub.2CHNH H H NO.sub.2 H CH.sub.3 117-119 68
+395.degree. (c = 0.2, CHCl.sub.3) 83 R A (CH.sub.3).sub.2CHNH H
CH.sub.3 NO.sub.2 H CH.sub.3 127-128 71 +414.degree. (c = 0.3,
CHCl.sub.3) 84 R D CH.sub.3(CH.sub.2).sub.2NH H H NO.sub.2 H
CH.sub.3 135-136 75 +363.degree. (c = 0.2, CHCl.sub.3) 85 R D
CH.sub.3(CH.sub.2).sub.2NH H CH.sub.3 NO.sub.2 H CH.sub.3 143-144
81 +375.degree. (c = 0.2, CHCl.sub.3) 86 R,S D
CH.sub.3(CH.sub.2).sub.3NH H H NO.sub.2 H CH.sub.3 148-152 91 87 R
A C.sub.6H.sub.5NH H CH.sub.3 NO.sub.2 H CH.sub.3 147-148 85
+362.degree. (c = 0.3, CHCl.sub.3) 88 R,S A CH.sub.3NH H Cl H H
CH.sub.3 90-91 76 89 R,S A CH.sub.3NH H H Cl H CH.sub.3 164-166 78
90 R,S A CH.sub.3NH H H F H CH.sub.3 80-83 64 91 R B
(CH.sub.3).sub.2N H H NO.sub.2 H CH.sub.3 92-96 74 +159.degree. (c
= 0.3, CHCl.sub.3) 92 R,S A CH.sub.3NH H H H H CH.sub.3 86-88 69 93
R,S A CH.sub.3NH H H NO.sub.2 H CH.sub.3CH.sub.2 188-189 75 94 R,S
A CH.sub.3NH H CH.sub.3O CH.sub.3O H CH.sub.3 185-186 72 95 R,S D
c-Pr--NH H H NO.sub.2 H CH.sub.3 169-172 70 96 R D c-Pr--NH H H
NO.sub.2 H CH.sub.3 83-90 75 +364.degree. (c = 0.2, CHCl.sub.3) 97
R D c-Pr--NH H CH.sub.3 NO.sub.2 H CH.sub.3 155-160 79 +319.degree.
(c = 0.3, CHCl.sub.3) 98 R,S C 1 H H NO.sub.2 H CH.sub.3 129-131 82
morpholyl 99 R,S C 1 H H NO.sub.2 H CH.sub.3 98-101 67 piperidyl
100 R,S E CH.sub.3ONH H H NO.sub.2 H CH.sub.3 200-201 74 101 R E
CH.sub.3ONH H H NO.sub.2 H CH.sub.3 142-143 74 +317.degree. (c =
0.2, CHCl.sub.3)
Example 102
(R,S)-7,8-Dimethoxy-4-methyl-3-methylthiocarbamoyl-1-(4-nitrophenyl)-3H-[2-
,3]benzodiazepine
[0169] A solution of 0.60 g (1.76 mmol) of starting compound I and
1.28 g (17.5 mmol) of methylisocyanate in 30 ml of dichloromethane
was heated under reflux for 26 h. The reaction mixture was quenched
with water and the two layers were separated. The organic phase was
extracted twice with water and after drying evaporated to give a
residue that was purified by column chromatography on silica gel
using a 2:1 mixture of hexane-ethyl acetate as eluent.
Recrystallization from 2-methoxyethanol (4 ml) gave after drying
0.50 g (69%) of the title product with mp.: 221-222.degree. C.
Examples 103-180
General Procedures for Reduction of the Nitro Group of the
Compounds Obtained in the Above Examples
[0170] Method A
[0171] 2 mmol of the nitro compound were dissolved in a mixture of
methanol-dichloromethane and after adding 10 mmol of 98% hydrazine
hydrate and 0.5-1.0 g of Raney Nickel catalyst the mixture was
stirred at r.t. for 1-24 h. After filtration of the catalyst the
filtrate was concentrated and the residue was treated with water
and the product was filtered off. Purification of the product was
done by recrystallization or column chromatography.
[0172] Method B
[0173] 0.6 g of a Raney Nickel slurry was prehydrogenated in a
(2:1) mixture of methanol and dichloromethane. Then 2.0 mmol of
nitro compound, dissolved in the above solvent mixture, was added
and hydrogenation was carried out at normal pressure. After
filtration of the catalyst and evaporation of the solvent the
residue was treated as in Method A.
[0174] Method C
[0175] 2.46 g (10.91 mmol) of tin(II) chloride dihydrate was added
to a solution of 1.82 mmol of the nitro compound in ethanol and the
mixture was stirred and heated to reflux for 3 h. After evaporation
of the solvent the residue was triturated with sodium hydrogen
carbonate solution and the product was extracted with ethyl
acetate. The organic phase was washed with brine, dried and
evaporated to give the crude product which was purified by column
chromatography.
[0176] The amino compounds prepared by the above procedures are
shown in the following two Tables:
TABLE-US-00011 TABLE 1 Enantiomers of
1-aminophenyl-7,8-dimethoxy-3-(aryl or carbamoyl)
substituted-4,5-dihydro-3H-[2,3]benzodiazepine derivatives .sup.1H
NMR data No. of Yield (%) (recorded at 500 MHz in DMSO-d.sub.6 at T
= 300K; Example Structure Method Mp (.degree.C.) [.alpha.].sub.D
other solvent is indicated.) 103 ##STR00023## C 239-242
93[.alpha.].sub.D:-657.degree.(c = 0.5,CHCl.sub.3) (Contains ca.
0.5 molequiv. ofethanol).sup.1H NMR .delta. 9.12 (s, 1H), 7.40 (dm,
J.sub.1 =8.4 Hz, 2H), 7.07 (s, 1H), 6.61(s, 1H), 6.59 (dm, J.sub.1
= 8.4 Hz,2H), 5.70 (s, 2H), 4.76 (m, 1H),3.84 (s, 3H), 3.63 (s,
3H), 2.92(dd, J.sub.1 = 13.8 Hz, J.sub.2 = 6.2 Hz,1H), 2.52 (dd,
J.sub.1 = 13.8 Hz, J.sub.2 =11.7 Hz, 1H), 1.21 (d, J = 6.0 Hz). 104
##STR00024## C amorphous 53[.alpha.].sub.D:-693.degree.(c =
0.5,CHCl.sub.3) (Contains ca. 0.5 molequiv. ofchloroform).sup.1H
NMR .delta. 9.12 (s, 1H), 7.37 (d, J =1.8 Hz, 1H), 7.20 (dd,
J.sub.1 = 8.2 Hz,J.sub.2 = 1.8 Hz, 1H), 7.06 (s, 1H),6.62 (d, J =
8.2 Hz, 1H), 6.59 (s,1H), 5.47 (s, 2H), 4.75 (m, 1H),3.83 (s, 3H),
3.62 (s, 3H), 2.92(dd, J.sub.1 = 13.6 Hz, J.sub.2 = 5.9 Hz,1H),
2.50 (1H, overlapping), 2.07(s, 3H), 1.20 (d, J = 5.9 Hz). 105
##STR00025## C 136-138 64 [.alpha.].sub.D:+691.degree.(c =
0.3,CHCl.sub.3) .sup.1H NMR .delta. 9.12 (s, 1H), 7.38 (d, J =1.8
Hz, 1H), 7.21 (dd, J.sub.1 = 8.3 Hz,J.sub.2 = 1.8 Hz, 1H), 7.07 (s,
1H),6.62 (d, J = 8.3 Hz, 1H), 6.60 (s,1H), 5.46 (s, 2H), 4.75 (m,
1H),3.84 (s, 3H), 3.62 (s, 3H), 2.91(dd, J.sub.1 = 14.2 Hz, J.sub.2
= 6.2 Hz,1H), 2.51 (dd, J.sub.1 =14.2 Hz, J.sub.2 =11.6 Hz, 1H),
2.08 (s, 3H), 1.20(d, J = 6.2 Hz). 106 ##STR00026## C 105-108
67[.alpha.].sub.D:-574.degree.(c = 0.5,CHCl.sub.3) .sup.1H NMR
.delta. 7.36 (d, J = 1.3 Hz, 1H),7.21 (dd, J.sub.1 = 8.3 Hz,
J.sub.2 = 1.3 Hz,1H), 7.06 (s, 1H), 6.62 (d, J =8.3 Hz, 1H), 6.58
(s, 1H), 5.45(s, 2H), 4.70 (m, 1H), 3.84 (s,3H), 3.62 (s, 3H), 2.89
(dd, J.sub.1 =13.9 Hz, J.sub.2 = 6.2 Hz, 1H), 2.48(dd, J.sub.1 =
13.9 Hz, J.sub.2 = 11.8 Hz,1H), 1.98 (s, 3H), 1.21 (d, J = 6.2 Hz).
107 ##STR00027## C 108-110 65[.alpha.].sub.D:-628.degree.(c =
0.2,CHCl.sub.3) .sup.1H NMR .delta. 9.14 (s, 1H), 7.61 (d, J =1.8
Hz, 1H), 7.29 (dd, J.sub.1 = 8.5 Hz,J.sub.2 = 1.8 Hz, 1H), 7.08 (s,
1H),6.82 (d, J = 8.5 Hz, 1H), 6.63 (s,1H), 5.95 (s, br, 2H), 4.78
(m,1H), 3.84 (s, 3H), 3.63 (s, 3H),2.94 (dd, J.sub.1 = 13.9 Hz,
J.sub.2 = 6.1Hz, 1H), 2.54 (dd, J.sub.1 = 13.9 Hz,J.sub.2 = 11.7
Hz, 1H), 1.21 (d, J = 6.2Hz, 3H). 108 ##STR00028## A 159-160
52[.alpha.].sub.D:-416.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 8.79 (s, 1H), 7.37 (dm, J.sub.1 =8.8 Hz, 2H), 7.11 (s, 1H),
6.63(s, 1H), 6.61 (dm, J.sub.1 = 8.8 Hz,2H), 5.74 (s, 2H), 5.05 (m,
1H),3.85 (s, 3H), 3.62 (s, 3H), 3.02(dd, J.sub.1 = 13.9 Hz, J.sub.2
= 4.9 Hz,1H), 2.67 (dd, J.sub.1 = 13.9 Hz, J.sub.2 =10.9 Hz, 1H),
1.23 (d, J = 6.1 Hz). 109 ##STR00029## A 160-162
61[.alpha.].sub.D:+419.degree.(c = 0.3,CHCl.sub.3) .sup.1H NMR
.delta. 8.79 (s, 1H), 7.37 (dm, J.sub.1 =8.8 Hz, 2H), 7.11 (s, 1H),
6.62(s, 1H), 6.60 (dm, J.sub.1 = 8.8 Hz,2H), 5.74 (s, 2H), 5.04 (m,
1H),3.85 (s, 3H), 3.61 (s, 3H), 3.02(dd, J.sub.1 = 13.9 Hz, J.sub.2
= 4.9 Hz,1H), 2.68 (dd, J.sub.1 = 13.8 Hz, J.sub.2 =10.9 Hz, 1H),
1.22 (d, J = 6.2 Hz). 110 ##STR00030## A 143
85[.alpha.].sub.D:-470.degree.(c = 0.5,CHCl.sub.3) .sup.1H NMR
.delta. 8.78 (s, 1H), 7.31 (d, J =2.1 Hz, 1H), 7.20 (dd, J.sub.1 =
8.6 Hz,J.sub.2 = 2.1 Hz, 1H), 7.10 (s, 1H),6.64 (d, J = 8.6 Hz,
1H), 6.61 (s,1H), 5.51 (s, 2H), 5.03 (m, 1H),3.85 (s, 3H), 3.60 (s,
3H), 3.01(dd, J.sub.1 =14.1 Hz, J.sub.2 = 5.5 Hz,1H), 2.66 (dd,
J.sub.1 = 14.1 Hz, J.sub.2 =10.8 Hz, 1H), 2.09 (s, 3H), 1.22(d, J =
6.1 Hz). 111 ##STR00031## A 129-134
63[.alpha.].sub.D:-255.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 8.81 (s, 1H), 7.51 (d, J =1.5 Hz, 1H), 7.26 (dd, J.sub.1 =
8.5 Hz,J.sub.2 = 1.5 Hz, 1H), 7.11 (s, 1H),6.83 (d, J = 8.5 Hz,
1H), 6.65 (s,1H), 5.96 (br, 2H), 5.09 (m, 1H),3.85 (s, 3H), 3.62
(s, 3H), 3.05(dd, J.sub.1 = 14.0 Hz, J.sub.2 = 4.5 Hz,1H), 2.72
(dd, J.sub.1 = 14.0 Hz, J.sub.2 =10.0 Hz, 1H), 1.07 (d, J = 6.0
Hz). 112 ##STR00032## A 229-230 95[.alpha.].sub.D:-486.degree.(c =
0.2,CHCl.sub.3) .sup.1H NMR .delta. 7.40 (dm, J.sub.1 = 8.9 Hz,2H),
7.26 (d, J = 3.7 Hz, 1H),7.08 (s, 1H), 6.81 (d, J = 3.7 Hz,1H),
6.63 (s, 1H), 6.61 (dm, J.sub.1 =8.9 Hz, 2H), 5.69 (s, 2H), 5.05(m,
1H), 3.85 (s, 3H), 3.61 (s,3H), 2.99 (dd, J.sub.1 = 13.9 Hz,
J.sub.2 =5.1 Hz, 1H), 2.65 (dd, J.sub.1 = 13.9Hz, J.sub.2 = 10.6
Hz, 1H), 1.18 (d, J =6.0 Hz). 113 ##STR00033## A 122-124
75[.alpha.].sub.D:-558.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.36 (dm, J.sub.1 = 7.6 Hz,2H), 7.04 (s, 1H), 6.61 (dm,
J.sub.1 =7.6 Hz, 2H), 6.61 (s, 1H), 5.62(s, 2H), 4.99 (m, 1H), 3.83
(s,3H), 3.61 (s, 3H), 2.94 (dd, J.sub.1 =13.7 Hz, J.sub.2 = 4.4 Hz,
1H), 2.62(dd, J.sub.1 = 13.7 Hz, J.sub.2 = 10.5 Hz,1H), 2.14 (s,
3H), 2.05 (s,3H), 1.15 (d, J = 6.1 Hz). 114 ##STR00034## A 116-118
74[.alpha.].sub.D:-527.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.34 (d, J = 2.0 Hz, 1H),7.25 (d, J = 3.4 Hz, 1H), 7.22(dd,
J.sub.1 = 8.2 Hz, J.sub.2 = 2.0 Hz, 1H),7.07 (s, 1H), 6.81 (d, J =
3.4 Hz,1H), 6.64 (d, J = 8.2 Hz, 1H),6.61 (s, 1H), 5.44 (s, br,
2H),5.04 (m, 1H), 3.84 (s, 3H), 3.60(s, 3H), 2.98 (dd, J.sub.1 =
13.9 Hz,J.sub.2 = 5.3 Hz, 1H), 2.63 (dd, J.sub.1 = 13.9Hz, J.sub.2
= 11.0 Hz, 1H), 2.08 (s,3H), 1.17 (d, J = 6.2 Hz, 3H). 115
##STR00035## A 116-117 85[.alpha.].sub.D:-281.degree.(c =
0.2,CHCl.sub.3) .sup.1H NMR (CDCl.sub.3) .delta. 7.66 (d, J =
2.0Hz, 1H), 7.43 (dd, J.sub.1 = 8.3 Hz,J.sub.2 =2.0 Hz, 1H), 7.31
(d, J = 3.6Hz, 1H), 6.81 (s, 1H), 6.77 (d,J = 8.3 Hz, 1H), 6.69 (s,
1H), 6.65(d, J = 3.6 Hz, 1H), 5.35 (m,1H), 4.32 (br, 2H), 3.95 (s,
3H),3.73 (s, 3H), 3.08 (dd, J.sub.1 = 14.1Hz, J.sub.2 = 4.5 Hz,
1H), 2.82 (dd,J.sub.1 = 14.1 Hz, J.sub.2 = 8.6 Hz, 1H), 1.28(d, J =
6.4 Hz, 3H). 116 ##STR00036## A 232-234
78[.alpha.].sub.D:-170.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.30 (d, J = 8.2 Hz, 2H),7.01 (s, 1H), 6.60 (s, 1H),
6.57(d, J = 8.2 Hz, 2H), 5.56 (s, 2H),4.89 (m, 1H), 4.05 (m, 1H),
3.93(m, 1H), 3.83 (s, 3H), 3.61 (s,3H), 3.13 (m, 1H), 3.06 (m,
1H),2.92 (dd, J.sub.1 = 14.2 Hz, J.sub.2 = 5.1Hz, 1H), 2.60 (dd,
J.sub.1 = 14.2 Hz,J.sub.2 = 9.5 Hz, 1H), 1.10 (d, J = 6.2 Hz). 117
##STR00037## C Foam(ca. 92- 95) 58[.alpha.].sub.D:-232.degree.(c =
0.2,CHCl.sub.3) .sup.1H NMR .delta. 7.28 (dm, J.sub.1 = 8.4 Hz,2H),
7.04 (s, 1H), 6.60 (s, 1H),6.57 (dm, J.sub.1 = 8.4 Hz, 2H), 5.66(s,
2H), 5.48 (d, J = 6.2 Hz, 1H),5.46 (d, J = 6.2 Hz, 1H), 4.63
(m,1H), 3.84 (s, 3H), 3.62 (s, 3H),2.93 (dd, J.sub.1 = 13.9 Hz,
J.sub.2 = 5.0Hz, 1H), 2.57 (dd, J.sub.1 = 13.9 Hz,J.sub.2 = 10.3
Hz, 1H), 1.18 (d, J = 6.2 Hz). 118 ##STR00038## C 194-197
71[.alpha.].sub.D:-327.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.24 (d, J = 2.0 Hz, 1H),7.12 (dd, J.sub.1 = 8.7 Hz,
J.sub.2 = 2.0 Hz,1H), 7.04 (s, 1H), 6.61 (d, J =8.7 Hz, 1H), 6.60
(s, 1H), 5.48(d, J = 6.0 Hz, 1H), 5.46 (d, J =6.0 Hz, 1H), 5.43 (s,
2H), 4.62(m, 1H), 3.84 (s, 3H), 3.61 (s,3H), 2.92 (dd, J.sub.1 =
14.1 Hz, J.sub.2 =5.3 Hz, 1H), 2.55 (dd, J.sub.1 = J.sub.2 =14.1
Hz, 1H), 2.06 (s, 3H), 1.19(d, J = 6.4 Hz). 119 ##STR00039## C
134-135 61[.alpha.].sub.D:-224.degree.(c = 0.2,CHCl.sub.3) .sup.1H
NMR .delta. 7.29 (dm, J.sub.1 = 8.6 Hz,2H), 7.04 (s, 1H), 6.60 (s,
1H),6.57 (dm, J.sub.1 = 8.6 Hz, 2H), 5.65(s, 2H), 5.48 (d, J = 6.1
Hz, 1H),5.46 (d, J = 6.1 Hz, 1H), 5.63 (m,1H), 3.84 (s, 3H), 3.62
(s, 3H),2.94 (dd, J.sub.1 = 13.9 Hz, J.sub.2 = 5.0Hz, 1H), 2.57
(dd, J.sub.1 = 13.9 Hz,J.sub.2 = 9.9 Hz, 1H), 1.18 (d, J = 6.1 Hz).
120 ##STR00040## B Foam(ca. 159-164)
62[.alpha.].sub.D:-323.degree.(c = 0.2,CHCl.sub.3) (Contains ca.
0.3 molequiv. ofethyl acetate).sup.1H NMR .delta. 11.75 (s, br,
1H), 7.51(d, J = 2.0 Hz, 1H), 7.25 (dd, J.sub.1 =8.5 Hz, J.sub.2 =
2.0 Hz, 1H), 7.05 (s,1H), 6.59 (d, J.sub.1 = 8.5 Hz, 1H),6.55 (s,
1H), 5.50 (s, br, 2H),4.47 (m, 1H), 3.84 (s, 3H), 3.62(s, 3H), 2.91
(dd, J.sub.1 = 13.9 Hz,J.sub.2 = 5.9 Hz, 1H), 2.49 (dd,overlapping,
1H), 1.22 (d, J = 6.0 Hz). 121 ##STR00041## A,B,C
140-144withtrans-formationat 108) 77
(A)[.alpha.].sub.D:-255.degree.(c = 0.5,CHCl.sub.3) .sup.1H NMR
.delta. 7.44 (dm, J.sub.1 = 8.6 Hz,2H), 7.01 (s, 1H), 6.57 (dm,
J.sub.1 =8.6 Hz, 2H), 6.55 (s, 1H), 6.15(q, J = 4.8 Hz, 1H), 5.63
(s,2H), 4.84 (m, 1H), 3.83 (s, 3H),3.62 (s, 3H), 2.79 (dd, J.sub.1
= 13.8Hz, J.sub.2 = 5.8 Hz, 1H), 2.62 (d, J =4.8 Hz, 3H), 2.41 (dd,
J.sub.1 = 13.8Hz, J.sub.2 = 11.7 Hz, 1H), 1.07 (d, J =6.4 Hz). 122
##STR00042## A 130-134 75[.alpha.].sub.D:+206.degree.(c =
0.2,CHCl.sub.3) .sup.1H NMR .delta. 7.44 (dm, J.sub.1 = 8.6 Hz,2H),
7.01 (s, 1H), 6.57 (dm, J.sub.1 =8.6 Hz, 2H), 6.54 (s, 1H), 6.15(q,
J = 4.9 Hz, 1H), 5.63 (s, 2H),4.83 (m, 1H), 3.83 (s, 3H), 3.61(s,
3H), 2.78 (dd, J.sub.1 = 13.9 Hz, J.sub.2 =5.9 Hz, 1H), 2.41 (dd,
J.sub.1 = J.sub.2 =13.9 Hz, 1H), 1.07 (d, J = 6.2 Hz). 123
##STR00043## A 147 84[.alpha.].sub.D:-285.degree.(c =
0.5,CHCl.sub.3) .sup.1H NMR .delta. 7.37 (d, J = 1.8 Hz, 1H),7.25
(dd, J.sub.1 = 8.2 Hz, J.sub.2 = 1.8 Hz,1H), 7.00 (s, 1H), 6.60 (d,
J =8.2 Hz, 1H), 6.53 (s, 1H), 6.13(q, J = 4.9 Hz, 1H), 5.39 (s,
2H),4.83 (m, 1H), 3.82 (s, 3H), 3.60(s, 3H), 2.79 (dd, J.sub.1 =
13.9 Hz, J.sub.2 =6.1 Hz, 1H), 2.61 (d, J = 4.9Hz, 1H), 2.39 (dd,
J.sub.1 = 13.9 Hz, J.sub.2 =11.9 Hz, 1H), 2.07 (s, 3H), 1.06(d, J =
5.9 Hz). 124 ##STR00044## A 157-159
78[.alpha.].sub.D:+308.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.41 (d, J = 1.7 Hz, 1H),7.26 (dd, J.sub.1 = 8.7 Hz,
J.sub.2 = 1.7 Hz,1H), 7.01 (s, 1H), 6.60 (d, J =8.7 Hz, 1H), 6.54
(s, 1H), 6.13(d, J = 4.2 Hz, 1H), 5,39 (s, 2H),4.84 (m, 1H), 3.83
(s, 3H), 3.61(s, 3H), 2.79 (dd, J.sub.1 = 13.7 Hz, J.sub.2 =5.4 Hz,
1H), 2.62 (d, J = 4.3Hz, 3H), 2.40 (dd, J.sub.1 = J.sub.2 = 13.7Hz,
1H), 2.08 (s, 3H), 1.07 (d, J = 6.4 Hz). 125 ##STR00045## A 119-12
82[.alpha.].sub.D:-125.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.72 (d, J = 2.0 Hz, 1H),7.32 (dd, J.sub.1 = 8.4 Hz,
J.sub.2 = 2.0Hz, 1H), 7.02 (s, 1H), 6.79 (d, J =8.4 Hz, 1H), 6.56
(s, 1H), 6.32(q, J = 4.7 Hz, 1H), 5.87 (s, 2H),4.88 (m, 1H), 3.83
(s, 3H), 3.62(s, 3H), 2.81 (dd, J.sub.1 = 14.0 Hz, J.sub.2 =6.0 Hz,
1H), 2.43 (dd, J.sub.1 = 14.0, J =11.9 Hz, 1H), 1.07 (d, J = 6.2
Hz). 126 ##STR00046## A 110-113 85[.alpha.].sub.D:-362.degree.(c =
0.2,CHCl.sub.3) .sup.1H NMR .delta. 7.24 (s, 2H), 7.00 (s,1H), 6.54
(s, 1H), 6.13 (q, J =4.2 Hz, 1H), 5.09 (s, 2H), 4.83(m, 1H), 3.83
(s, 3H), 3.60 (s,3H), 2.79 (dd, J.sub.1 = 13.8 Hz, J.sub.2 =5.6 Hz,
1H), 2.62 (d, J = 4.8 Hz,3H), 2.38 (dd, J.sub.1 = J.sub.2 = 13.8
Hz,1H), 2.10 (s, 6H), 1.07 (d, J =5.9 Hz). 127 ##STR00047## A
122-124 84[.alpha.].sub.D:-266 .degree.(c = 0.2,CHCl.sub.3) .sup.1H
NMR .delta. 7.42 (dm, J.sub.1 = 8.7 Hz,2H), 7.01 (s, 1H), 6.56 (dm,
J.sub.1 =8.7 Hz, 2H), 6.55 (s, 1H), 6.25(t, J = 4.9 Hz, 1H), 5.64
(s, 2H),4.83 (m, 1H), 3.82 (s, 3H), 3.61(s, 3H), 3.08 (m, 2H), 2.78
(dd, J.sub.1 =13.9 Hz, J.sub.2 = 5.9 Hz, 1H), 2.41(dd, J.sub.1 =
J.sub.2 = 13.9 Hz, 1H), 1.06(d, J = 6.4 Hz), 1.01 (t, J = 7.2 Hz)
128 ##STR00048## A 107-110 65[.alpha.].sub.D:-300.degree.(c =
0.2,CHCl.sub.3) .sup.1H NMR .delta. 7.36 (s, 1H), 7.26 (d, J =8.1
HZ, 1H), 7.01 (s, 1H), 6.61(d, J = 8.1 Hz, 1H), 6.55 (s, 1H),6.22
(t, J = 5.2 Hz), 5.39 (s,2H), 4.84 (m, 1H), 3.83 (s, 3H),3.61 (s,
3H), 3.09 (m, 2H), 2.80(dd, J.sub.1 = 13.0 Hz, J.sub.2 = 5.3
Hz,1H), 2.41 (dd, J.sub.1 = J.sub.2 = 13.0 Hz,1H), 2.08 (s, 3H),
1.07 (d, J =6.0 Hz), 1.02 (t, J = 7.1 Hz). 129 ##STR00049## A
101-104 73[.alpha.].sub.D:-203.degree.(c = 0.2,CHCl.sub.3) .sup.1H
NMR .delta. 7.42 (dm, J.sub.1 = 8.0 Hz,2H), 7.01 (s, 1H), 6.58 (dm,
J.sub.1 =8.0 Hz, 2H), 6.56 (s, 1H), 6.25(t, J = 5.8 Hz, 1H), 5.63
(s, br,2H), 4.85 (m, 1H), 3.83 (s, 3H),3.62 (s, 3H), 3.03 (m, 2H),
2.80(dd, J.sub.1 = 13.7 Hz, J.sub.2 = 5.0 Hz,1H), 2.43 (dd, J.sub.1
= 13.7 Hz, J.sub.2 =11.7 Hz, 1H), 1.43 (m, 2H), 1.07(d, J = 6.0
Hz), 0.82 (t, J = 7.6Hz). 130 ##STR00050## A 92-95
71[.alpha.].sub.D:-237.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.34 (d, J = 2.1 Hz, 1H),7.24 (dd, J.sub.1 = 8.6 Hz,
J.sub.2 = 2.1 Hz,1H), 7.00 (s, 1H), 6.61 (d, J =8.6 Hz, 1H), 6.55
(s, 1H), 6.22(t, J = 6.4 Hz, 1H), 5.39 (s, br,2H), 4.83 (m, 1H),
3.82 (s, 3H),3.60 (s, 3H), 3.02 (m, 2H), 2.80(dd, J.sub.1 = 13.7
Hz, J.sub.2 = 5.9 Hz,1H), 2.41 (dd, J.sub.1 = 13.7 Hz, J.sub.2
=11.7 Hz, 1H), 2.07 (s, 3H), 1.43(m, 2H), 1.06 (d, J = 6.0 Hz,
3H),0.82 (t, J = 7.3 Hz, 3H). 131 ##STR00051## A 115-117
74[.alpha.].sub.D:-226.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.26 (d, J = 2.0 Hz, 1H),7.20 (dd, J.sub.1 = 8.3 Hz,
J.sub.2 = 2.0 Hz,1H), 7.00 (s, 1H), 6.63 (d, J =8.3 Hz, 1H), 6.58
(s, 1H), 5.88(d, J = 7.7 Hz, 1H), 5.42 (s, br,2H), 4.85 (m, 1H),
3.82 (s, 3H),3.73 (m, 1H), 3.60 (s, 3H), 2.81(dd, J.sub.1 = 13.5
Hz, J.sub.2 = 5.3 Hz,1H), 2.43 (dd, J.sub.1 = 13.5 Hz, J.sub.2
=11.7 Hz, 1H), 2.07 (s, 3H), 1.14(d, J = 6.4 Hz, 3H), 1.06 (d, J
=6.4 Hz, 6H). 132 ##STR00052## A 116-119
80[.alpha.].sub.D:-222.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.38 (dm, J.sub.1 = 8.3 Hz,2H), 7.01 (s, 1H), 6.57 (dm,
J.sub.1 =8.3 Hz, 2H), 6.57 (s, 1H), 6.14(d, J = 2.2 Hz, 1H), 5.64
(s, br,2H), 4.85 (m, 1H), 3.83 (s, 3H),3.62 (s, 3H), 2.80 (dd,
J.sub.1 = 13.6Hz, J.sub.2 = 5.4 Hz, 1H), 2.50 (m,overlapping), 2.42
(dd, J.sub.1 = 13.6Hz, J.sub.2 = 11.7 Hz, 1H), 1.08 (d, J =6.2 Hz),
0.6-0.4 (m, 4H). 133 ##STR00053## A 112-114
78[.alpha.].sub.D:-260.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.32 (d, J = 1.8 Hz, 1H),7.22 (dd, J.sub.1 = 8.3 Hz,
J.sub.2 = 1.8 Hz,1H), 7.01 (s, 1H), 6.61 (d, J =8.3 Hz, 1H), 6.56
(s, 1H), 6.13(d, J = 2.9 Hz, 1H), 5.40 (s, br,2H), 4.84 (m, 1H),
3.83 (s, 3H),3.61 (s, 3H), 2.80 (dd, J.sub.1 = 13.6Hz, J.sub.2 =
5.6 Hz, 1H), 2.50 (m,overlapping), 2.40 (dd, J.sub.1 = 13.6Hz,
J.sub.2 = 11.6 Hz, 1H), 2.07 (s,3H), 1.08 (d, J = 6.0 Hz,
3H),0.6-0.4 (m, 4H). 134 ##STR00054## A 258-260
80[.alpha.].sub.D:-434.degree.(c = 0.2,CHCl.sub.3) .sup.1H NMR
.delta. 7.36 (dm, J.sub.1 = 8.2 Hz,2H), 7.00 (s, 1H), 6.57 (s,
1H),6.56 (dm, J.sub.1 = 8.2 Hz, 2H), 5.67(s, 2H), 4.46 (m, 1H),
3.82 (s,3H), 3.63 (s, 3H), 2.76 (dd, J.sub.1 =12.9 Hz, J.sub.2 =
5.6 Hz, 1H), 2.35(dd, J.sub.1 = J.sub.2 = 12.9 Hz, 1H), 1.16(d, J =
4.8 Hz) 135 ##STR00055## C 143-145 26[.alpha.].sub.D:-260.degree.(c
=
0.1,CHCl.sub.3) (Contains ca. 0-4 molequiv. ofethyl acetate).sup.1H
NMR .delta. 9.21 (s, 1H), 7.47 (dm,J.sub.1 = 9.0 Hz, 2H), 7.02 (s,
1H), 6.56(s, 1H), 6.55 (dm, J.sub.1 = 9.0 Hz,2H), 5.57 (s, 2H),
4.76 (m, 1H),3.83 (s, 3H), 3.62 (s, 3H), 3.53(s, 3H), 2.80 (dd,
J.sub.1 = 13.0 Hz,J.sub.2 = 5.3 Hz, 1H), 2.43 (dd, J.sub.1 =
J.sub.2 =13.0 Hz, 1H), 1.12 (d, J = 6.5 Hz).
TABLE-US-00012 TABLE 2 Racemic 1-aminophenyl-7,8-dialkoxy-3- (aryl
or carbamoyl) substituted-4,5-dihydro-3H- [2,3]benzodiazepine
derivatives No. of Example Structure Method Mp (.degree. C.) Yield
(%) 136 ##STR00056## A 119-122 69 137 ##STR00057## A 122-124 88 138
##STR00058## A 120-122 74 139 ##STR00059## A 121-124 87 140
##STR00060## A 109-113 76 141 ##STR00061## A 121-123 84 142
##STR00062## A 166-168 94 143 ##STR00063## A 184-188 77 144
##STR00064## A 152-153 71 145 ##STR00065## A 220-222 73 146
##STR00066## A 208-209 76 147 ##STR00067## A 108-110 74 148
##STR00068## A 125-130 69 149 ##STR00069## A 108-113 78 150
##STR00070## A 100-105 74 151 ##STR00071## A 209-211 72 152
##STR00072## A 260-262 86 153 ##STR00073## B 135-137 80 154
##STR00074## A 159-163 64 155 ##STR00075## C 227-229 61 156
##STR00076## C 233-236 78 157 ##STR00077## C 234-237 58 158
##STR00078## C 232-235 56 159 ##STR00079## C 158-162 56 160
##STR00080## C 117-119 59 161 ##STR00081## A 103-107 80 162
##STR00082## A 152-155 73 163 ##STR00083## A 164-167 87 164
##STR00084## A 160-162 72 165 ##STR00085## A 203-205 78 166
##STR00086## A 243-246 56 167 ##STR00087## A 113-115 80 168
##STR00088## A 105-107 73 169 ##STR00089## A 103-108 67 170
##STR00090## A 88-91 74 171 ##STR00091## A 169-170 71 172
##STR00092## A 109-111 85 173 ##STR00093## A 120-123 65 174
##STR00094## A 204-207 94 175 ##STR00095## A 119-122 92 176
##STR00096## A 119-120 78 177 ##STR00097## A 124-127 62 178
##STR00098## A 129-132 67 179 ##STR00099## C 173-174 36 180
##STR00100## C 235-237 70
Examples 181-191
General Procedure for Synthesis of 2,3-Benzodiazepines Containing
1-Acylamino-Phenyl Group
[0177] To a stirred solution of a 2,3-benzodiazepine containing an
aminophenyl substituent from one of the previous examples, in
dichloromethane, an excess of acetic anhydride (or in case of
Example 191 methyl isocyanate) was added and the reaction mixture
was kept at r.t. After completion of the reaction, the mixture was
washed with sodium hydrogen carbonate solution and water, then
dried and evaporated to dryness.
[0178] The following compounds were prepared by this procedure:
TABLE-US-00013 Configur- No. of ation Yield (%) Example Structure
at C-4 Mp (.degree. C.) [.alpha.].sub.D 181 ##STR00101## R, S
130-134 54 182 ##STR00102## R, S 209-211 77 183 ##STR00103## R
156-158 90-50.degree.(c = 0.2CHCl.sub.3) 184 ##STR00104## R 238-239
54-143.degree.(c = 0.2CHCl.sub.3) 185 ##STR00105## R 229-231
62-64.degree.(c = 0.2CHCl.sub.3) 186 ##STR00106## R 213-215
65-82.degree.(c = 0.2CHCl.sub.3) 187 ##STR00107## R, S 150-151 53
188 ##STR00108## R, S 207-210 87 189 ##STR00109## R, S 152-154 80
190 ##STR00110## R 234-236 75-621.degree.(c = 0.2CHCl.sub.3) 191
##STR00111## R, S 160-162 67
BIOLOGICAL EXAMPLES
[0179] The biological activity of the compounds of formula (I) are
exemplified by the following methods.
[0180] In Vitro Tests
[0181] The new 2,3-benzodiazepine atypical antipsychotic agents of
formula (I) of the present invention influence dopaminergic
neurotransmission by a unique indirect fashion, differently from
both the first and second generation antipsychotics. The in vitro
binding profile of these compounds (Table 3) differs from that of
the first generation antipsychotics which bind to dopaminergic
receptors and second generation antipsychotics, representatives of
which show affinity for dopaminergic, serotonergic, or adrenergic
receptors.
TABLE-US-00014 TABLE 3 The in vitro binding profile of some
compounds of invention and clozapine to central dopaminergic,
serotonergic and adrenergic receptors Com- pounds (Number of
Example) D.sub.1 D.sub.2 D.sub.3 D.sub.4 5HT.sub.1A 5HT.sub.2A
.alpha..sub.1 .alpha..sub.2 121 >10.sup.4 >10.sup.4
>10.sup.4 >10.sup.4 >10.sup.4 >10.sup.4 >10.sup.4
>10.sup.4 123 >10.sup.4 >10.sup.4 >10.sup.4
>10.sup.4 >10.sup.4 >10.sup.4 >10.sup.4 >10.sup.4
104 >10.sup.4 >10.sup.4 >10.sup.4 >10.sup.4
>10.sup.4 >10.sup.4 >10.sup.4 >10.sup.4 110
>10.sup.4 >10.sup.4 >10.sup.4 >10.sup.4 >10.sup.4
>10.sup.4 >10.sup.4 >10.sup.4 Cloza- 290 130 240 47 140
8.9 4 33 pine* Data are expressed in nM *Miyamoto, S., Therapeutics
of Scizophrenia. In: Davis, K. L., Charney, D., Coyle, J. T. et al,
eds. Neuropsychopharmacology: The 5th Generation of Progress.
Philadelphia, Pa: Lippincott Williams & Wilkins, 2002, p 778.
D.sub.2 receptor binding was determined using rat striatal
membranes (ligand: [.sup.3H]sulpirid, D.sub.1 and D.sub.2 binding
in human recombinant CHO cells (ligands: [.sup.3H]SCH-23390 and
[.sup.3H]spiperone, resp.), D.sub.4 binding in human recombinant
CHO-K1 cells (ligand: [.sup.3H]spiperone), 5HT.sub.1A in rat
hippocampal membranes (ligand: [.sup.3H]-8-OH-DPAT, 5HT.sub.2A in
rat cerebral cortical membranes (ligand: [.sup.3H]ketanserin,
.alpha..sub.1 and .alpha..sub.2 binding in rat cerebral cortical
membranes (ligands: [.sup.3H]prazosin and [.sup.3H]yohimbine,
resp.).
[0182] Acute administration of atypical antipsychotics results in
enhanced accumulation of dihydroxyphenylalanine (DOPA) in the
eminentia mediana in rats after the inhibition of DOPA
decarboxylase. In contrast, DOPA accumulation is not altered by the
typical antipsychotics (Andersson, G, Albinsson, A, Pettersson, G,
Arzneimittelforschung. 1990, 40, 237; Gudelsky, G. A., Meltzer, H.
Y. Neuropsychopharmacology, 1989, 2, 45).
[0183] The effect of the compound of Example 121 on
DOPA-accumulation was measured by analyzing the levels of DOPA in
eminentia mediana. Sprague-Dawley (240-280 g, male) rats were
treated (ip) with compound of Example 121 or with reference
compounds (chlorpromazine, clozapine) at doses indicated in Table
4. Thirty min after the treatments they received NSD-1015 (100
mg/kg), a DOPA-decarboxylase inhibitor, and the animals were
sacrificed 30 min later. Eminentia mediana (EM), were dissected out
from the brains on ice-cold plates and kept at -70.degree. C. until
they were assayed for DOPA by HPL-EC. Statistical analysis was
carried out using one-way ANOVA followed by Duncan test.
TABLE-US-00015 TABLE 4 Effect of compound of Example 121 on DOPA
accumulation in EM Treatment & dose ip. (mg/kg) DOPA levels
(Referents & DOPA levels (pg/tissue compound of Example
(pmol/mg prot) block) Saline 49.9 .+-. 5.4 422 .+-. 30 CPZ.; 10
56.4 .+-. 4.1 n.t. CLOZ; 20 87.4 .+-. 9.5** n.t. 121; 10 n.t. 484
.+-. 34 121; 20 n.t. 652 .+-. 69* 121; 40 94.0 .+-. 11.4** n.t. CPZ
= Chlorpromazine; CLOZ = Clozapine Summary data of two separate
experiments. Bars represent the group means .+-. SEM. Animals in
the CPZ-group were treated with NSD-1015 90 min after the CPZ
treatment. Statistically different (*p < 0.05; **p < 0.01)
from the saline group. n.t. = not tested
[0184] As Table 4 shows, the compound of Example 121 and the
atypical antipsychotic clozapine significantly increased the levels
of DOPA in the EM of rats. Chlorpromazine, a typical antipsychotic
had no effect.
[0185] The unique spectrum of in vitro activity of new atypical
2,3-benzodiazepines of formula (I) is presented in Table 5.
TABLE-US-00016 TABLE 5 In vitro efficacy of new atypical
2,3-benzodiazepines of formula (I) Inhibition in % (conc: 10 .mu.M)
Compounds of Adenosine Melatonin (MT2) Example transporter receptor
121 87 80 123 90 64 104 96 80 110 94 95
[0186] It is well known from the literature that both adenosine and
melatonin influence dopaminergic neurotransmission. (Weiss, S. M.
et al, Neurology, 2003, 61, S88-S93; Miyamoto, S., Therapeutics of
Scizophrenia. In: Davis, K. L., Charney, D., Coyle, J. T. et al,
eds. Neuropsychopharmacology: The 5th Generation of Progress.
Philadelphia, Pa.: Lippincott Williams & Wilkins, 2002, pp
775-807; Zisapel, N. Cell. Mol. Neurobiol. 2001, 21, 605). Thus,
the atypical antipsychotic efficacy of the compounds of formula (I)
may be related to the activity on the adenosine transporter and
melatonin receptor.
[0187] The compounds prepared according to examples 121, 123, 104,
110, 112, and 183 were also tested in an in vitro "spreading
depression" model to determine the AMPA antagonistic effect of the
compounds of formula (I). Specifically, the inhibition of AMPA
induced "spreading depression" caused by glutamate agonists (i.e.,
AMPA or kainate) was studied in isolated chicken retina. By way of
background, the "spreading depression" model has shown that AMPA
antagonists prolong the latency of the development of the
"spreading depression" caused by AMPA (5 .mu.M).
[0188] The compounds of the present invention inhibited the
AMPA-induced "spreading depression" with an IC.sub.50 value of
greater than 20 .mu.M. When these results were compared to the
results shown for AMPA antagonists in Table 1 of U.S. Pat. No.
6,858,605, it was shown that the compounds of the present invention
do not exhibit AMPA antagonism.
[0189] In Vivo Tests
[0190] The in vivo antipsychotic effect of the compounds is
exemplified in the following experiments. Test substances were
suspended in 2% Tween-80.
[0191] Anti-apomorphine effects were investigated in the climbing
test in mice mediated through the mesolimbic and stereotypy test in
rats mediated through the nigrostriatal system. Conventional
antipsychotics antagonize both apomorphine-induced behaviours,
while known atypical antipsychotics are weaker against apomorphine
stereotypy.
[0192] The climbing test was carried out according to Protais et
al. (Protais, P. et al. Psychopharmacologia, 1976, 50, 1.)
Stereotyped behavior was induced in food deprived (for 16 hours)
male CD1 mice weighing 20-25 g body by apomorphine HCl (SIGMA) in a
s.c. dose of 2 mg/kg. Mice were placed individually into cylinders
having 12 cm diameter and consisting of vertical bars of 2 mm
diameter where apomorphine treated animals tended to adopt a
vertical position in contrary to vehicle treated controls. Test
substances were applied ip. 30 min before apomorphine.
[0193] 10 and 20 min after apomorphine treatment the climbing
behaviour was evaluated by scores of 0-2. 10 mice/group were used.
The scores of the two readings were summed individually, meaned and
compared to the control. The ED.sub.50 values were calculated by
Litchfield-Wilcoxon's method (Litchfield Jr. J. T., Wilcoxon, F. J.
Pharmacol. Exp. Ther. 1949, 96, 49,).
[0194] Apomorphine-induced stereotypy was investigated according to
Costall and Naylor (B. Costall and R. J. Naylor, Eur. J. Pharmacol.
1972, 18, 95) in male CD1 mice of 20-25 g body weight after 16
hours deprivation of food. 30 min before treatment mice were
individually placed into small, transparent acrylic cages for
habituation. Test substances were administered orally in a volume
of 0.1 ml/10 g. 30 min later mice were treated with apomorphine HCl
(SIGMA) in a subcutaneous dose of 2 mg/kg. Stereotyped behaviour
was observed in every 5th min for 60 min and scored from 0-5. The
scores were summed individually, meaned and compared to the control
group. The ED.sub.50 values were calculated by
Litchfield-Wilcoxon's method (J. Pharmacol. Exp. Ther. 1949, 96,
49,).
[0195] Results are summarized in Table 6.
TABLE-US-00017 TABLE 6 Inhibition of apomorphine-induced climbing
and stereotyped behavior in mice Compounds (Referents and Climbing
Stereotypy compounds of ED.sub.50 (mg/kg ED.sub.50 (mg/kg Example)
ip.) po.) Chlorpromazine 1.2 3.6 Clozapine 2.64 22.9 121 4.31 3.54
123 9.2 7.52 104 7.7 6.97 110 14.6 3.5 112 25 Not available 183 8.7
Not available
[0196] As the data of the table show, clozapine was more active in
climbing than in the stereotypy assay while the test compounds of
the invention inhibited both behaviors, similarly to
chlorpromazine.
[0197] In order to investigate the potential side effect profile,
the catalepsy test in rats has been carried out according to
Costall and Naylor (Costall, B., Naylor, R. J.
Arzneimittelforschung/Drug Res., 1973, 23, 674).
[0198] Catalepsy is defined as a failure to correct an externally
imposed, unusual posture over a prolonged time. Neuroleptics which
have direct inhibitory action on the nigrostriatal dopamine system
induce catalepsy. It may be reflected by the Parkinson-like
extrapyramidal symptoms seen clinically with administration of
classical antipsychotics. The experiments were carried out in male
CDBR rats weighing 300-400 g. The volume of administration was 0.25
ml/100 g body weight. The animals were starved for 16 hours before
treatment, water was delivered ad libitum. After intraperitoneal
administration of the test substances, the forepaws of the rats
were placed on a horizontal stainless steel bar elevated to 10 cm
high, while the hind paws remained on a metal plate. The
semi-automatic 5-channel catalepsy meter measured the time spent in
this unusual posture by an electronic stop-clock. The catalepsy
time was scored from 0 to 5 according to the time spent in the
unusual posture. The scores were observed in every 30 min for 4
hours and the total scores of 8 readings were summed up
individually. Means of groups were calculated.
TABLE-US-00018 TABLE 7 Cataleptogenic activity in rats Compounds
(Referents and compounds of Dose (mg/kg ip)/ Example) Catalapsy
scores Chlorpromazine 10:8.7 Clozapine 10:0.14 121 10:0 123 40:0
104 40:0 110 10:0.375
[0199] Data of Table 7 show that compounds of the invention lack
cataleptogenic potential similar to the atypical antipsychotic
clozapine while the classical chlorpromazine induces severe
catalepsy.
[0200] For measuring the antipsychotic potential in a non-perturbed
dopamine system the pole jumping assay was used (Cook, L., Catania,
A. C. Fed. Proc. 1964, 23, 818.)
[0201] This method is an active avoidance learning test. Long-Evans
rats, weighing 250-450 g, were used in the experiments. Rats are
placed in a box (25.times.25.times.25 cm) on a grid floor in the
center of which there is a pole. After a latency period, light is
turned on for a given time then the floor is electrified to deliver
an unpleasant footshock. Rats may learn to avoid the shock by
jumping up to grasp the pole. As soon as the rat jumps up the light
and shock are turned off. Each light-on period lasted for 15 s,
shock time for 30 s with an intertrial interval of 15 s. 30 such
trials per day were repeated during the learning period until
animals reach a minimum of 80% avoidance rate. During the
experimental sessions 20 trials/day were run. Test substances were
administered ip. in a volume of 0.25 ml/100 g body weight.
Significances were calculated by Student's t test.
[0202] During the experiments even those rats which did not jump
onto the pole during the light-on period, they jumped during the
footshock phase excluding influence on motor function:
antipsychotics suppress only the avoidance procedure and not the
escape responding (See Table 8).
TABLE-US-00019 TABLE 8 Effect on conditioned avoidance responses:
pole jumping test in rats Compounds (Referent and compounds of
Example) MED (mg/kg ip) Clozapine 2 121 5 123 2 104 15 110 2 MED =
minimal effective dose (stat. sign.)
[0203] According to the data, some representatives of the compounds
of the invention show similar activity to clozapine.
[0204] Alterations in the mesocortical dopaminergic tract are
thought to be responsible for the negative symptoms of
schizophrenia (flattening of affect, poverty of speech, lack of
volition and drive, loss of feeling, social withdrawal and
decreased spontaneous movement). The best animal model of these
symptoms is the behavioral changes induced by PCP (phencyclidine).
The PCP-induced stereotypy and hypermotility was investigated in
mice according to Ljungberg and Ungerstedt (Ljungberg, T.,
Ungerstedt, U. Pharmacol. Biochem. Behav., 1985, 23, 479,) and
Jawitt (Jawitt, D. C. Amer. J. Psychiatry, 1991, 145, 1301). The
stereotypy experiments were carried out in male CD1 mice weighing
20-25 g. The animals were starved for 16 hours before treatment
without limitation of water availability. In the stereotypy
studies, 30 min before treatment, mice were individually placed
into small, transparent acrylic cages for habituation. Test
substances were administered orally in a volume of 0.1 ml/10 g. 30
min later mice were treated with PCP with an intraperitoneal dose
of 7 mg/kg. Stereotyped behavior was observed every 5th min for 60
min and scored from 0 to 4. The scores were summed individually,
averaged and compared to the control group.
[0205] The motor activity was measured in a 4-channel activity
meter. The apparatus consisted of acrylic cages
(40.times.40.times.32 cm) equipped with 16 pairs of infrared
photocells. The photocells' beam, when broken, signaled a count,
which was then recorded by a computer. A 5 mg/kg intraperitoneal
dose of PCP was administered 5 min before the experiment. This dose
of PCP induces 110-120% increase of the spontaneous motor activity.
Test substances were administered orally 15 min before experiment,
and mice were investigated individually in the experimental cages
for 60 min. 10 mice/group were used. The total counts for each
experimental group were compared to the vehicle treated control
group.
[0206] In both studies the ED.sub.50 values were calculated by the
Litchfield-Wilcoxon's method (J. Pharmacol. Exp. Ther. 1949, 96,
49).
TABLE-US-00020 TABLE 9 Effect in the PCP-induced stereotypy model
in mice Compounds (Reference and PCP- PCP- compounds of stereotypy
hypermotility Example) ED.sub.50 mg/kg po. Chlorpromazine N.D. 1.86
Clozapine 3.76 1.81 121 1.56 0.87 123 1.07 0.62 104 1.12 0.73 110
2.38 1.4 N.D. = not determined
[0207] As the data of Table 9 show, selected compounds show a
stronger inhibitory activity on PCP-induced behavioral changes
compared either to chlorpromazine or clozapine indicating a better
chance for influencing the negative symptoms of schizophrenia, too.
The results further indicate that the compounds of the invention
are active orally.
[0208] The antipsychotic activity of compounds 121 and 183 were
evaluated using PCP-induced disruption of pre-pulsed inhibition
("PPI") in C57B1/6J mice. In general, it was found that Clozapine
as well as Compound 121 (2.5 and 5 mg/kg) and Compound 183 (5, 10,
and 15 mg/kg) significantly reversed phenylcyclohexylpiperidine
(PCP)-induced disruption of PPI.
[0209] Male C57B1/6J mice from Jackson Laboratories (Bar Harbor,
Me.) were used in this study. Mice were received at 6-weeks of age.
Upon receipt, mice were assigned unique identification numbers
(tail marked) and were group housed in OPTImice cages. All animals
remained housed in groups of four during the remainder of the
study. All mice were acclimated to the colony room for at least two
weeks prior to testing and were subsequently tested at an average
age of 8 weeks of age. During the period of acclimation, mice were
examined on a regular basis, handled, and weighed to assure
adequate health and suitability. Mice were maintained on a 12/12
light/dark cycle with the light on at 6:00 a.m. The room
temperature was maintained between 20 and 23.degree. C. with a
relative humidity maintained between 30% and 70%. Food and water
were provided ad libitum for the duration of the study. In each
test, animals were randomly assigned across treatment groups.
[0210] All compounds were injected i.p. at a dose volume of 10
ml/kg. Compound 121 (0.5, 2.5, 5 mg/kg) and Compound 183 (1.5, 5,
10, 15 mg/kg) were dissolved in 3% polysorbate tween 80 and sterile
isotonic saline. Clozapine (1 mg/kg) was dissolved in 10% DMSO.
Phenylcyclohexylpiperidine (PCP) (8 mg/kg) was dissolved in sterile
water.
[0211] The acoustic startle measured an unconditioned reflex
response to external auditory stimulation. PPI consisting of an
inhibited startle response (reduction in amplitude) to an auditory
stimulation following the presentation of a weak auditory stimulus
or prepulse, has been used as a tool for the assessment of
deficiencies in sensory-motor gating, such as those seen in
schizophrenia. Mice were placed in the PPI chambers (Med
Associates) for a 5 min session of white noise (70 dB)
habituation.
[0212] After the acclimation period the test session was
automatically started. The session started with a habituation block
of 6 presentations of the startle stimulus alone, followed by 10
PPI blocks of 6 different types of trials. Trial types are: null
(no stimuli), startle (120 dB), startle plus prepulse (4, 8 and 12
dB over background noise i.e. 74, 78 or 82 dB) and prepulse alone
(82 dB). Trial types were presented at random within each
block.
[0213] Each trial started with a 50 ms null period during which
baseline movements were recorded. There was a subsequent 20 ms
period during which prepulse stimuli were presented and responses
to the prepulse measured. After further 100 ms the startle stimuli
were presented for 40 ms and responses recorded for 100 ms from
startle onset. Responses were sampled every ms. The inter-trial
interval was variable with an average of 15 s (range from 10 to 20
s). In startle alone trials the basic auditory startle was measured
and in prepulse plus startle trials the amount of inhibition of the
normal startle was determined and expressed as a percentage of the
basic startle response (from startle alone trials), excluding the
startle response of the first habituation block.
[0214] For PCP-disrupted PPI, mice were pretreated with Vehicle,
Compound 121, Compound 183, or Clozapine and placed in holding
cages for 30 min following which mice were injected with either PCP
or water and placed back in holding cages for 30 min prior to
testing.
[0215] Data were analyzed by analysis of variance (ANOVA) followed
by post-hoc comparisons with Fisher Tests when appropriate. An
effect was considered significant if p<0.05. Data are
represented as the mean and standard error to the mean. Mice that
showed mean startle less than 100 or a response that was 2 standard
deviations above or below the mean were removed from the final
analysis.
[0216] The high doses of both Compound 121 (5 mg/kg) and Compound
183 (15 mg/kg) caused sedation and lethargy in the mice.
[0217] The effects of Compound 121, Compound 183, and Clozapine on
PCP-induced disruption of PPI are shown in FIG. 1. Repeated
measures ANOVA found a significant treatment effect. Compared to
the vehicle alone, PCP significantly disrupted PPI. Pretreatment
with Clozapine, Compound 121 (2.5 and 5 mg/kg) and all doses of
Compound 183 significantly reversed this disruption.
[0218] The effects of compounds 121 and 183, administered orally,
were also evaluated in the PCP induced locomotor activity test.
Compound 121 was designated as "Compound A" and Compound 183 was
designated as "Compound B" for purposes of this study. In general,
the study aimed to test Compounds A and B for potential
antipsychotic activity in PCP treated mice.
[0219] The drugs used were as follows:
[0220] Compounds A & B were dissolved in 3% Tween: Compound A:
1, 3, 6, 10, and 15 mg/kg; Compound B: 3, 7, 14, 28, and 40 mg/kg;
Compounds A+B were administered by gavage.
[0221] Clozapine (1 mg/kg) was dissolved in 10% DMSO.
[0222] PCP (5 mg/kg) was dissolved in sterile injectable water.
[0223] The open field ("OF") test assessed both anxiety and
locomotor behavior. The open field chambers are Plexiglas square
chambers (27.3.times.27.3.times.20.3 cm; Med Associates Inc., St
Albans, Vt.) surrounded by infrared photobeams
(16.times.16.times.16) to measure horizontal and vertical activity.
The analysis was configured to divide the open field into a center
and periphery zone. Distance traveled was measured from horizontal
beam breaks as the mouse moved whereas rearing activity was
measured from vertical beam breaks.
[0224] Mice were brought to the activity experimental room for at
least 1 hr acclimation to the experimental room conditions prior to
testing. Eight animals are tested in each run. Mice treated with
Vehicle, Compound A and B were placed in holding cages for 30
minutes; then placed in the OF chamber for the 30 minute baseline
assessment following which, they were injected with PCP (5 mg/kg)
or water and placed back in the OF chambers for a 60-minute
session. Animals that were injected with either 10% DMSO or
Clozapine were placed in the OF immediately for a 30-min baseline
assessment, followed by injection of PCP for the 60 minute session.
At the end of each OF test session, the OF chambers were thoroughly
cleaned.
[0225] Data were analyzed by analysis of variance (ANOVA) followed
by post-hoc comparisons with Fisher Tests when appropriate. Data
was analyzed to show baseline activity (activity during the 30 min
prior to PCP injection) and PCP-induced activity (activity during
the 60 min after PCP injection). Statistical outliers that fell
above or below 2 standard deviations from the mean were removed
from the final analysis. An effect was considered significant if
p<0.05. Data are represented as the mean and standard error to
the mean.
[0226] The effect of Compounds A & B on PCP-induced locomotion
is shown in FIG. 2. Statistical analysis by ANOVA found a
significant treatment effect. Post hoc analysis found that
clozapine and all doses of Compounds A & B significantly
decreased the PCP induced locomotion, compared to their respective
vehicles.
[0227] The results of the different pharmacological investigations
mentioned above show that the compounds of formula (I) of the
invention exert an antipsychotic character and they can be regarded
as atypical antipsychotics
* * * * *